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Int. J. Mol. Sci. 2017, 18(12), 2589; doi:10.3390/ijms18122589

Review
The Role of Resveratrol in Cancer Therapy
1
College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
2
Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
3
Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
4
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
5
Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA 6009, Australia
6
Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA
*
Authors to whom correspondence should be addressed.
Received: 15 November 2017 / Accepted: 29 November 2017 / Published: 1 December 2017

Abstract

:
Natural product compounds have recently attracted significant attention from the scientific community for their potent effects against inflammation-driven diseases, including cancer. A significant amount of research, including preclinical, clinical, and epidemiological studies, has indicated that dietary consumption of polyphenols, found at high levels in cereals, pulses, vegetables, and fruits, may prevent the evolution of an array of diseases, including cancer. Cancer development is a carefully orchestrated progression where normal cells acquires mutations in their genetic makeup, which cause the cells to continuously grow, colonize, and metastasize to other organs such as the liver, lungs, colon, and brain. Compounds that modulate these oncogenic processes can be considered as potential anti-cancer agents that may ultimately make it to clinical application. Resveratrol, a natural stilbene and a non-flavonoid polyphenol, is a phytoestrogen that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anti-cancer properties. It has been reported that resveratrol can reverse multidrug resistance in cancer cells, and, when used in combination with clinically used drugs, it can sensitize cancer cells to standard chemotherapeutic agents. Several novel analogs of resveratrol have been developed with improved anti-cancer activity, bioavailability, and pharmacokinetic profile. The current focus of this review is resveratrol’s in vivo and in vitro effects in a variety of cancers, and intracellular molecular targets modulated by this polyphenol. This is also accompanied by a comprehensive update of the various clinical trials that have demonstrated it to be a promising therapeutic and chemopreventive agent.
Keywords:
Resveratrol; cancer; molecular targets; apoptosis; chemoprevention; therapy

1. Introduction

Cancer is one of the most commonly diagnosed diseases, and its related morbidity and mortality constitute a very significant health problem worldwide. Although great efforts have been made to discover a cure, cancer remains a very prominent cause of mortality in humans, and effective treatment remains a formidable challenge. An estimated 1.6 million new cancer diagnoses and approximately 600,000 cancer-related deaths are expected in the United States in 2017 alone [1]. Despite several novel improvements in diagnosis and surveillance, the overall cancer survival rate has not improved. Several personalized care medicines, such as targeted therapies, have emerged, providing improved clinical outcomes for cancer patients [2]. However, some of the recent advanced improvements in treating cancer have resulted in development of acquired resistance to chemotherapeutic agents [3]. Carcinogenesis is a multistep and multifactorial process involving the occurrence of clear and discrete molecular and cellular alterations; there are distinct but closely connected phases of initiation, promotion, and progression [4,5,6]. Current cancer therapies, e.g., chemotherapy, targeted agents, radiation, surgery, and immunosuppression, have limitations resulting from the development of resistance to the therapy [7]. The identification of protective molecules without side effects remains a primary objective in the fight against cancer. The other options aim at the early detection of cancer in the benign stage, which can help with its proper management [8].
Since ancient times, natural products have been used to prevent several chronic diseases, including cancer [9,10,11,12,13,14,15,16,17,18]. Revived interest in phytochemicals obtained from dietary or medicinal plant sources has provided an alternative source of bioactive compounds that can be used as preventive or therapeutic agents against a variety of diseases [19,20,21,22,23]. Phytochemicals such as phytoestrogens have been reported to modulate multiple cellular-signaling pathways, with no or minimal toxicity to normal cells [24,25]. The application of substances to prevent or delay the development of carcinogenesis has been termed chemoprevention [4], and there is burgeoning interest in the use of natural compounds as possible chemopreventive and therapeutic agents for human populations. Resveratrol is increasing in prominence because it has cancer-preventive and anti-cancer properties [25,26,27,28]. A non-flavonoid polyphenol, resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a phytoalexin that naturally occurs in many species of plants, including peanuts, grapes, pines, and berries, and assists in the response against pathogen infections [29]. Interestingly, Chinese and Japanese traditional medicine also contain it, in the form of extracts such as those obtained from Polygonum cuspidatum, which can be used to treat inflammation, headaches, cancers, and amenorrhea.
The structure of resveratrol is stilbene-based and comprises two phenolic rings connected by a styrene double bond to produce 3,4′,5-trihydroxystilbene, which occurs in both the trans- and cis-isoforms (Figure 1). The trans-isoform is the major isoform, and represents the most extensively studied chemical form. Exposure to heat and ultraviolet radiation can cause the trans-isoform to convert into the cis-isoform, whose structure closely resembles that of the synthetic estrogen diethylstilbestrol. Because of this, resveratrol has also been classified as a phytoestrogen. Its biosynthetic pathway begins with a reaction between the malonyl CoA and coumaryl derivative, which is catalyzed by the enzyme stilbene synthase [30]. Resveratrol is easily available in a regular diet and has numerous health-augmenting properties, as well as some naturally occurring analogs, such as viniferins, pterostilbene, and piceid [31]. Additionally, some semi-synthetic resveratrol analogs have also been found to have certain pharmacological benefits, including chemoprevention actions, anti-oxidant effects, and anti-aging properties [32,33,34]. It had also been shown that resveratrol can reverse drug resistance in a variety of tumor cells by sensitizing them to chemotherapeutic agents [35,36]. In particular, it has been reported that trans-resveratrol and its glucoside have wide-ranging effects, including cardioprotective, anti-oxidative, anti-inflammatory, estrogenic/anti-estrogenic, and anti-tumor properties [37,38]. Moreover, the antimicrobial effects [39] of trans-resveratrol have been found to be useful in the management of cognitive disorders such as dementia [40,41]. This review, however, will concentrate primarily on resveratrol and discuss its diverse anti-cancer effects in various preclinical and clinical studies.

2. In Vitro Pharmacological Properties and Anti-Cancer Effects of Resveratrol

It has been shown that resveratrol possesses multifaceted salubrious properties, e.g., anti-inflammatory, anti-oxidative, and anti-aging qualities [42,43,44]. Resveratrol is a constituent of red wine, and therefore it is often postulated that resveratrol is a significant element in the French Paradox, the reduced risk of cardiovascular disease in French populations despite the high intake of saturated fats; that has been associated with high red wine consumption [45]. After Jang et al. [46] found that resveratrol inhibited carcinogenesis in a mouse-skin cancer model in 1997, a wealth of publications followed. It has been shown that resveratrol has in vitro cytotoxic effects against a large range of human tumor cells, including myeloid and lymphoid cancer cells, and breast, skin, cervix, ovary, stomach, prostate, colon, liver, pancreas, and thyroid carcinoma cells [25,47,48,49]. Resveratrol affects a variety of cancer stages from initiation and promotion to progression by affecting the diverse signal-transduction pathways that control cell growth and division, inflammation, apoptosis, metastasis, and angiogenesis.

3. Anti-Tumor-Initiation Activity

Neoplasia initiation concerns the alteration or mutation of genes resulting spontaneously from or caused by exposure to a carcinogenic agent, which finally results in mutagenesis [50]. Oxidative stress plays a dominant part in the causation of carcinogenesis [51]. Reactive oxygen species (ROS) can react with DNA in addition to chromatin proteins, resulting in several types of DNA damage [52,53]. In fact, chemical carcinogens cannot damage DNA until they are metabolized by phase-I biotransformation enzymes, especially cytochrome P450, in cells and converted to reactive electrophiles. In addition, carcinogen-DNA adduct formation gives rise to chemical carcinogenesis [54]. This initiation stage is irreversible but can be prevented by inhibiting the activity and expression of certain cytochrome P450 enzymes and augmenting the activity of phase-II detoxification enzymes, which transform carcinogens into less toxic and soluble products [55,56].
It has been found that resveratrol can inhibit events linked to the initiation of tumors. For instance, resveratrol treatment suppressed free radical formation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human leukemia HL-60 cells [57]. The diverse anti-oxidant properties of resveratrol have already been described previously [58,59]. Resveratrol is an excellent scavenger of hydroxyls and superoxides, as well as radicals induced by metals/enzymes and generated by cells [59]. It also protects against lipid peroxidation within cell membranes and damage to DNA resulting from ROS [59]. Furthermore, resveratrol functions as an anti-mutagen, as shown by its inhibition of the mutagenicity of N-methyl-N’-nitro-N-nitrosoguanidine in the Salmonella typhimurium strain TA100 [60]. It has been proposed that resveratrol can be a possible chemopreventive agent, and its anti-mutagenic and anti-carcinogenic properties have been demonstrated in several models [9,61,62].
In addition, resveratrol can inhibit 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)–induced expression of cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1), as well as their catalytic actions, in human breast epithelial Michigan cancer foundation (MCF)-10A cells [63]. Resveratrol can also abrogate the CYP1A activity induced by environmental aryl hydrocarbon benzo[a]pyrene (B[a]P) and catalyzed by directly suppressing the CYP1A1/1A2 enzyme activity and the signal-transduction pathway that up-regulates the expression of carcinogen-activating enzymes in human breast cancer MCF-7 and liver cancer HepG2 cells [64]. It has been reported that resveratrol also has inhibitory effects on aryl hydrocarbon receptor (AhR)–mediated activation of phase-I enzymes. The canonical AhR-dependent signaling pathway is thought to contribute to carcinogenic initiation by phase-I enzyme–activated polycyclic aromatic hydrocarbons (PAH). Briefly, PAH can bind to the AhR and facilitate its translocation into the nucleus, where the AhR develops into a heterodimer with AhR nuclear translocator (ARNT). The AhR/ARNT heterodimer then attaches to and transactivates xenobiotic response element–driven phase-I/II enzyme promoters, and initiates carcinogenesis. It has been postulated that resveratrol’s inhibition of AhR signaling can suppresses this initiation process. For example, resveratrol caused inhibition of TCDD-induced recruitment of AhR and ARNT to the CYP1A1/1A2 and CYP1A1/1B1 promoter in HepG2 and MCF-7 cells, respectively, culminating in decreased expression [65]. Resveratrol also reduced TCDD-induced, AhR-mediated CYP1A1 expression in gastric cancer AGS cells [66]. Resveratrol could therefore modulate the activity and expression of some cytochrome P450 enzymes, and thereby help prevent cancer by limiting the activation of pro-carcinogens.
It has also been found that resveratrol increases both the activity and expression of NAD(P)H: quinone oxidoreductase-1 (NQO1), a carcinogen-detoxifying phase-II enzyme, in human leukemia K562 cells [67]. In addition, resveratrol was also found to induce the activity of the phase-II detoxifying metabolic enzyme quinone reductase (QR) within mouse liver-cancer Hepa 1c1c7 cells [68]. Within breast cancer cells, resveratrol induced QR expression via the estrogen receptor β (ER-β), thereby protecting against oxidative damage to DNA [69]. Resveratrol also augments the activity and expression of anti-oxidant and phase-II detoxifying enzymes through the activation of nuclear factor E2–related factor 2 (Nrf2). Nrf2 generally remains sequestered in the cytoplasm by binding Kelch-like ECH-associated protein 1 (Keap1). When Nrf2 is induced by dietary phytochemicals like resveratrol, it dissociates itself from Keap1 and translocates into the nucleus. Nrf2 thereafter attaches to the anti-oxidant response element (ARE) found in the promoters of several genes that encode phase-II enzymes, and thus regulates their transcriptional activation [70,71]. Resveratrol has been also shown to up-regulate the expression of heme oxygenase-1 (HO-1) via Nrf2 activation in PC12 cells. Resveratrol induction of the expression of NQO1 in TCDD-treated normal human breast epithelial MCF10F cells involved Nrf2, resulting in the formation of DNA adducts being suppressed [72].
Resveratrol also caused an increase in NQO1 after estradiol-3,4-quinone (E2-3,4-Q) or 4-hydroxyestradiol (4-OHE2) treatment in MCF10F cells [73]. In addition, resveratrol-induced Nrf2 signaling can lead to an increased expression of HO-1, NQO1, and the glutamate cysteine ligase (GCL) catalytic subunit in human bronchial epithelial HBE1 cells treated with cigarette-smoke extracts [74]. Resveratrol also restored glutathione levels in human lung cancer A549 cells treated with cigarette-smoke extracts, by Nrf2-induced GCL expression [75]. In leukemia K562 cells resveratrol increased NQO1 expression and induced Nrf2/Keap1/ARE binding to NQO1 promoter [67].

4. Anti-Tumor-Promotion Activity

Tumor promotion involves clonally enlarging initiated cells to create a continuously proliferating, premalignant lesion. Tumor promoters generally alter gene expression, resulting in increased cell proliferation and decreased death of cells [76]. Studies conducted in vitro have discovered that resveratrol exerts an anti-proliferative activity by inducing apoptosis. Of these, resveratrol modifies the balance of cyclins as well as cyclin-dependent kinases (CDKs), resulting in cell cycle inhibition at G0/G1 phase. For example, a link has been found between the inhibition of cyclin D1/CDK4 by resveratrol and cell cycle arrest in the G0/G1 phase within different cancer cells [77,78,79,80]. Resveratrol was also shown to increase the levels of cyclin A and E, with cell cycle arrest in the G2/M and S phases [81,82]. Similar findings have indicated that resveratrol causes the arrest of cell cycles and activation of the p53-dependent pathway [83,84,85].
p53, a tumor-suppressor protein, is an element critically linked to transcription, and is closely connected to the regulation of apoptosis and cell proliferation; and also acts as a key mediator in the prevention of carcinogenesis [86]. p53 that has been activated binds DNA and stimulates the expression of certain genes, e.g., WAF1/CIP1 encoding for p21, which belongs to the group of CDK inhibitors that are vital to the inhibition of cell growth [87]. Resveratrol reduced the development of human skin cancer A431 cells by downregulating the expression of cyclin D1, cyclin D2, and cyclin E, inhibiting the activities and/or expression of CDK2, CDK4, and CDK6, and upregulating the expression of p21. Resveratrol also suppressed the proliferation of breast cancer MCF-7 and human prostate cancer DU-145 cells [88] via modulating CDK4 and cyclin D1 expression, which have been linked to the induction of p21 and p53. When used to treat A549 cells, resveratrol caused S phase arrest, reduced retinoblastoma protein (Rb) phosphorylation, and induced p21 and p53 protein expression [89]. It has also been demonstrated that resveratrol limits the expression of Rb, another tumor-suppressor protein involved in the G1/S transition in normal conditions [79,82,85].
It has also been shown that resveratrol’s anti-proliferative activity involves the stimulation of apoptosis within cancer cells [90,91,92]; it has been proposed that apoptosis activation could be a probable mechanism for chemotherapeutic agents to destroy cancerous cells [93,94]. In many human tumors, apoptosis has been found to be impaired, which suggests that the disruption of apoptotic functions significantly contributes to a normal cell being transformed into a tumor cell. Apoptosis is cell death that has been programmed, and a genetically regulated physiological mechanism to eliminate damaged or abnormal cells. It is also significant as a physiological-growth-control regulator and a tissue-homeostasis moderator in embryonic, fetal, and adult tissues. Apoptotic cells can be identified by regular biochemical and morphological properties, including membrane blebbing, cell shrinkage, nuclear DNA fragmentation, chromatin condensation, and formation of apoptotic bodies [95].
Apoptosis can be activated via two major pathways: the mitochondria-apoptosome-mediated intrinsic pathway and the death receptor–induced extrinsic pathway. [96,97]. The triggering of death receptors in the tumor necrosis factor (TNF) receptor superfamily, e.g., Fas (CD95/APO-1), or of TNF-related apoptosis-inducing ligand (TRAIL) receptors causes the initiator caspase-8 to be activated, which can mediate the apoptosis signal via direct cleavage of downstream effector caspases such as caspase-3 [98]. Caspases are an ubiquitous family of cysteine proteases, and have critical functions in apoptosis as upstream initiators and downstream effectors [99]. The intrinsic pathway is triggered by the dispensation of apoptogenic factors such as Omi/HtrA2, Smac/DIABLO, cytochrome c, apoptosis-inducing factors (AIFs), endonuclease G, caspase-2, or caspase-9 from the mitochondrial intermembrane space [100]. The dissemination of cytochrome c into the cytosol activates caspase-3 via the creation of the cytochrome c/apoptotic protease-activating factor-1 (Apaf-1)/caspase-9-containing apoptosome complex; Omi/HtrA2 and Smac/DIABLO encourage caspase activation by neutralizing the effects of inhibitors of apoptotic proteins (IAPs) [100,101].
Crosstalk also occurs between the two apoptotic pathways. For instance, Fas is connected to the intrinsic pathway that is regulated via the activation of caspase-8 to cause cleavage of the BID protein, causing cytochrome c to be released from the mitochondria [102,103]. Various apoptotic cell-death mechanisms have been propounded [104,105]. One logical approach to reducing the incidence of cancer appears to be the targeting of critical parts of apoptosis regulatory pathways, including the IAPs (in particular XIAP, cIAP1, and cIAP2), the anti-apoptotic Bcl-2 family of proteins, nuclear factor-kappa B (NF-κB), survivin, tyrosine kinases, caspases, and critical signaling pathways (phosphoinositide 3-kinase (PI3K)/AKT, STAT3/5, and MAPK pathways) [7,13,20,106,107,108,109,110,111,112]. Resveratrol prompts the death of tumor cells by modulating diverse signal transduction pathways via regulation of the levels of Fas and Fas-ligand (FasL) [113,114]. Resveratrol also enhances FasL expression in HL-60 cells, and the resveratrol-induced apoptosis is Fas signaling-dependent [113].
Similar outcomes have also been observed in breast [113] and colon cancer cells [114]. Mechanisms of cell death that are independent of Fas and caused by cytotoxic agents have also been propounded [115,116], and apoptosis induced by doxorubicin occurs through a Fas-independent pathway [116]. Likewise, it has been shown that resveratrol exhibits Fas-independent apoptosis in another leukemic THP-1 cell line [117]. It has also been observed that resveratrol induced the death of leukemia CEM-C7H2 cells in a Fas-independent manner, as demonstrated by the absence of apoptotic change in the presence of antibodies antagonistic to Fas or FasL [118]. Furthermore, resveratrol effectively triggered apoptosis in Fas-resistant Jurkat human leukemia cells [118].
It has been shown that resveratrol induces cell death in some cancer cells by changing the proteins of the Bcl-2 family [119]. The inhibition of anti-apoptotic proteins of the Bcl-2 family, and activation of pro-apoptotic proteins such as Bad, Bak or Bax, by resveratrol has also been shown to be a mechanism for caspase activation and cytochrome c release [120,121]. Interestingly, these effects may be correlated with p53 activation [122,123,124,125]. For instance, resveratrol increased the cytoplasmic concentration of calcium in human breast cancer MDA-MB-231 cells, which activated p53 and caused different pro-apoptotic genes to be transcribed [126].
It has also been shown that resveratrol induces apoptosis via inhibiting the PI3K/Akt/mTOR pathway [79,120,127,128,129,130,131], modulating the mitogen-activated protein kinase pathway (MAPK) [129,130,132], and inhibiting NF-κB activation [133,134]. Resveratrol triggered apoptosis within human T-cell acute lymphoblastic leukemia MOLT-4 cells by abrogating Akt phosphorylation, and subsequently preventing GSK3β from being activated [135]. Similarly, resveratrol induced apoptosis in ovarian, [136] breast, [137] uterine, [138] prostate, [120] and multiple myeloma cells [121], via inhibiting Akt phosphorylation. Chen et al. [139] determined that resveratrol inhibited the phosphorylation of PI3K/Akt (i.e., PI3K/Akt inactivation) in prostate cancer cells, resulting in decreased Forkhead box protein (FOXO) activation. Resveratrol’s inhibition of the serine/threonine protein kinase Akt has been identified in anti-cancer activity modulated by the activation of FOXO3a in human breast cancer cells, because FOXO3a was not found to be activated by Akt [140].
It has been suggested that resveratrol interferes with the MAPK pathway. In cervical carcinoma cells, resveratrol inhibited the activation of p38, JNK1, and ERK2 [141]. Resveratrol activates ERK1/2 at low concentrations (1 pM–10 μM), but at higher concentrations (50–100 μM) can inhibit MAPK in human neuroblastoma SH-SY5Y cells [142]. In contrast, resveratrol activates ERK1/2 in prostate [143], breast [144,145], glial [146], head and neck [147], and ovarian cancer cells [148]. MAPKs in a constitutively active state are necessary to maintain the malignant state; however, short-term activation of MAPK may drive the cells to apoptosis [149]. It has also been reported that resveratrol causes activation of other kinases, like JNK and p38 [150]. Notably, it has been shown that the resveratrol’s anti-tumor effects require p53 activation that is MAPK-induced, as well as the subsequent induction of apoptosis [151,152,153].
Resveratrol induces apoptosis in, and obstructs proliferation of, human multiple myeloma cells via inhibiting the constitutive activation of NF-κB through abrogating the IκB-α kinase activation, and thus down-regulating certain anti-apoptotic and pro-proliferation gene products, such as survivin, cIAP-2, cyclin D1, XIAP, Bcl-xL, Bfl-1/A1, Bcl-2, and TNF-α receptor-associated factor 2 (TRAF2) [121,154]. The constitutive activation of NF-κB, defined as the persistence of NF-κB within the nucleus, is apparent in a wide range of cancer cells [155,156,157,158]. Active NF-κB drives the expression of a plethora of genes that guard against apoptotic cell death and maintain cell proliferation [158]. Deregulation of the NF-κB signaling pathway can cause increased apoptosis as NF-κB modulates anti-apoptotic genes, e.g., TRAF1 and TRAF2, and thus changes the activities of caspases critical to the majority of apoptotic processes [159]. It has been determined that resveratrol can suppress NF-κB-regulated gene products connected with inflammation matrix metalloproteinase (MMP)-3, MMP-9, cyclooxygenase-2 (COX-2), and vascular endothelial growth factor (VEGF), inhibit anti-apoptotic proteins (Bcl-xL, Bcl-2, and TRAF1), and activate cleaved-caspase-3 [160].
Resveratrol also causes inhibition of signal transducers and activators of transcription 3 (STAT3), which adds to its pro-apoptotic and anti-proliferative potential [121]. STAT3 is a critical element in inflammation-related tumorigenesis as it promotes the proliferation, survival, invasion, angiogenesis, and metastasis of tumor cells [112,161]. The activation of NF-κB also promotes inflammation, proliferation, and tumorigenesis [162]. STAT3 and NF-κB are two central transcriptional factors linking tumorigenesis and inflammation; both of them can be activated as a response to certain stimuli, such as cytokines, growth factors, and stress signals. Abnormal signaling of STAT3 or NF-κB in malignant cells is therefore a promising target of therapy. STAT3 and NF-κB are activated via distinct pathways, and move to the nucleus to effect transcriptional activity. STAT3 and NF-κB that are constitutively activated by acetylation and/or phosphorylation in tumor cells, have been closely linked to both cancer development and progression [163,164]. Kim et al. reported that resveratrol caused inhibition of the nuclear translocation of STAT3 in renal cell carcinoma [165].
Interestingly, Wen et al. showed that inhibiting NF-κB nuclear translocation caused apoptosis in resveratrol-treated medulloblastoma cells [166]. It has been suggested that cross-talk occurs between the STAT3 and NF-κB pathways, because of the release of IL-6 and other cytokines, and because of the activation of cytokine receptors. STAT3 and NF-κB actually co-regulate many inflammatory and oncogenic genes, like IL-1β, Bcl-xL, Myc, COX-2, and cyclin D1 [161]. By their possible functional interaction, STAT3 and NF-κB collaboratively promote the development of tumors via inducing the expression of pro-tumorigenic genes [167]. The dysregulation of these genes because of the constant activation of both STAT3 and NF-κB in tumors and the tumor microenvironment is critical to tumor progression. Inflammation can regulate angiogenesis and cellular proliferation, and inhibits apoptosis [168]. It has also been reported that resveratrol inhibits the processes of several inflammatory enzymes in vitro, e.g., COXs and lipoxygenases (LOXs) [169,170]. It was shown in a recent study that resveratrol could radiosensitize and block the STAT3 signaling pathway by inducing SOCS-1, thereby reducing STAT3 phosphorylation and proliferation in head and neck tumor cells [171].

5. Anti-Tumor-Progression Activity

Tumor progression involves several processes such as that lead to tumor metastasis. Several genes are mutated or deleted that sustain the development of aggressive tumors. The invasion and metastasis of cancer cells involve the destruction of the extracellular matrix (ECM) and basement membrane, by proteolytic enzymes, such as matrix metalloproteinases (MMPs). Of these enzymes, MMP-2 and MMP-9 are overexpressed within a variety of malignant tumors modulating cell invasion and metastasis [172]. Tissue inhibitor metalloproteinase proteins (TIMPs), on the other hand, are a protein group comprising TIMP-1, -2, -3, and -4 acting as natural MMP inhibitors [173]. To sustain their swift growth, invasive tumors also need to grow new blood vessels via a process called angiogenesis. During angiogenesis, endothelial cells can be stimulated by various growth factors, including fibroblast growth factor (FGF) and VEGF, and travel to where the new blood vessels are required. Blocking the development of new blood vessels causes the supply of nutrients and oxygen to be reduced and, as a result, the size of the tumor and metastasis may also be reduced.
It has been suggested that resveratrol plays a role in inhibiting the expression of MMP (mainly MMP-9) [174,175,176,177] and angiogenesis markers such as VEGF, EGFR or FGF-2 [79,178]. Resveratrol reduced the phorbo-12-myristate 13-acetate (PMA)-induced migration and invasion ability of liver cancer HepG2 and Hep3B cells. In HepG2 cells, resveratrol up-regulated TIMP-1 protein expression and down-regulated MMP-9 activity, while the activities of MMP-2 and MMP-9 were decreased, along with a rise in the protein-expression level of TIMP-2 in Hep3B cells [175]. HepG2 cells treated with TNF-α expressed a high level of MMP-9, which resveratrol suppressed considerably via down-regulating the expression of NF-κB, resulting in the expression of MMP-9 protein being suppressed and the invasive capability of HepG2 cells being diminished [174]. Resveratrol treatment of breast cancer MDA-MB231 cells caused inhibition of the epidermal growth factor (EGF)-induced elevation of cell migration, and of the expression of MMP-9. Resveratrol also reduced a subunit of the mammalian mediator complex for transcription (called MED28, and whose over-expression can increase migration), via the EGFR/PI3K signaling pathways [176]. Both VEGF and hypoxia-inducible factor-1α (HIF-1α) are over-expressed in several human tumors and their metastases, and are closely linked to a more aggressive tumor phenotype. It has been reported that resveratrol suppresses the expression of VEGF and HIF-1α in human ovarian cancer cells via abrogating the activation of the PI3K/Akt and MAPK signaling pathways [179]. Resveratrol caused inhibition of the expression of these molecules, which suggests that it could be part of an efficacious anti-cancer therapy for preventing cancer and its metastasis [180,181,182].
Malignant transformation may be linked to signaling pathways during tumorigenesis, thereby promoting epithelial-to-mesenchymal transition (EMT), which may in turn increase the invasiveness and motility of cancer cells, and trigger cancer metastasis [183,184]. Many studies have shown that resveratrol suppresses the development of tumor invasion and metastasis through inhibiting signaling pathways associated with EMT [185]. Transforming growth factor-beta (TGF-β) is a widely known cytokine that encourages invasion, proliferation, EMT, and angiogenesis of cancer cells, and the TGF-β/Smad signaling pathway can activate EMT during cancer metastasis [186,187]. Resveratrol (20 μM) inhibited TGF-β-induced EMT in A549 lung cancer cells by augmenting the expression of E-cadherin and attenuating the expression of vimentin and fibronectin, as well as the EMT-inducing transcription factors Slug and Snail [188]. Qing Ji et al. showed that resveratrol inhibited EMT induced by TGF-β, as well as the invasion and metastasis of colorectal cancer, via reducing Smad2/3 expression [189]. NF-κB can also promote EMT, in addition to cancer migration and invasion [190,191,192].
Several studies have shown that NF-κB is a significant EMT regulator for different types of cells [190,191,192,193,194]. The roles for NF-κB have been found to be linked to the expression of various genes related to EMT, such as ZEB1, Snail, E-cadherin, MMP-7, MMP-9, and MMP-13 [192,193,195,196]. NF-κB can also be activated through PI3K/Akt signaling pathway to drive EMT and cancer-cell metastasis. Resveratrol suppressed the metastatic potential of pancreatic cancer PANC-1 cells in vitro by regulating factors related to EMT (vimentin, E-cadherin, N-cadherin, MMP-2, and MMP-9) and modulating the activation of PI3K/Akt/NF-κB pathways [197].

6. Pre-Clinical Studies

Resveratrol has also been reported to possess a significant anti-cancer property in various preclinical animal models (Table 1).

7. Skin Cancer

The first preclinical study of the anti-cancer or chemopreventive effect of resveratrol was reported in a two-stage, 7,12-Dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoyl-13-acetate (TPA)-promoted mouse-skin carcinogenesis model [46]. Thereafter, several in vivo skin cancer studies have been performed with DMBA/TPA [46,199,200,201,235,236], DMBA alone, [237,238,239], TPA alone [240,241,242], ultraviolet B radiation (UVB) exposure [202,203,204,243], benzo[a]pyrene (BP) [237], and xenograft models [198]. In the DMBA/TPA models, resveratrol treatment reduced the incidence [46,199,200,201,235], multiplicity [46,199,201,235], and tumor volume [201,235,236], and delayed the onset of tumorigenesis [201]. Resveratrol prevented DMBA/TPA-induced skin cancer from developing in mice, and was effective at all stages of carcinogenesis.
Soleas et al. discovered that resveratrol was somewhat efficacious in reducing the rate of tumor formation and the number of animals that developed skin tumors induced by DMBA [200]. Resveratrol inhibited tumor promotion in the DMBA–TPA mouse-skin carcinogenesis model, possibly because (at least in part) of its anti-oxidant properties [199]. Resveratrol administration restored glutathione (GSH) levels, superoxide dismutase (SOD), GSH peroxidase, and catalase activities to control values (mice without UVB irradiation) [244]. Furthermore, resveratrol exerted an anti-oxidant effect with a reduction in H2O2 and lipid peroxidation in the skin [202]. It has been shown that the anti-proliferative effects of this stilbene can be regulated by cell-cycle regulatory proteins such as the expression of CDK2, 4, and 6, cyclin D1 and D2, and proliferating cell nuclear antigen (PCNA), while the expression of p21 was increased [203].
Resveratrol effectively hindered the development of DMBA/TPA-induced mouse-skin tumors by inducing apoptosis, which was indicated by the induction of cytochrome c release, the expression of Bax, p53, and Apaf-1, and the inhibition of Bcl-2 [201]. Afaq et al. determined that resveratrol had the ability to reduce edema and inflammation resulting from short-term UVB exposure in the skin of SKH-1 hairless mice, possibly because of the inhibition of ornithine decarboxylase (ODC) [202]. Treatment with resveratrol both before and after exposure to UVB suppressed development of skin tumor [204]. Resveratrol’s anti-tumor properties have also been linked to lower expression levels of TGF-β1 and augmented expression levels of E-cadherin [243]. Oral gavage of resveratrol hindered the development of a mouse melanoma (B16BL6 cell line) xenograft carried in mice, with decreased expression of Akt [245]. In a murine model of the human cutaneous skin squamous carcinoma A431 cell-line xenograft, resveratrol treatment reduced the volume of the tumor, raised the expression levels of ERK and p53, and lowered the expression level of survivin [198]. Nevertheless, resveratrol did not reduce the tumor growth of other melanoma cell lines, including A375, B16M, and DM738 xenografts in mice [246,247].

8. Breast Cancer

Resveratrol has exhibited anti-cancer and chemopreventive properties in various animal breast cancer models. Models of chemically induced mammary-gland carcinogenesis using N-methyl-nitrosourea (MNU) [212], estradiol [248], or DMBA [46], in addition to models of spontaneous mammary tumors with HER-2/neu-overexpressed [207] or Brca1-mutated (K14cre; Brca1F/F; p53F/F) mice [249], have been employed to determine resveratrol’s preventive or curative effects. Oral administration of resveratrol was also found to reduce tumorigenesis induced by N-nitoso-N-methylurea (NMU) in rats [212,250].
Resveratrol, in a xenograft animal model, inhibited the development of ER-β–positive MDA-MB-231 and estrogen receptor (ER)-α–negative tumor explants, raised apoptosis, and lowered angiogenesis in nude mice [208]. However, resveratrol did not affect the in vivo development and metastasis of transplanted ER-α–negative 4T1 murine mammary cancer cells in nude mice [251]. Bove et al. studied resveratrol’s in vivo effect with doses of 1–5 mg/kg per day administered intraperitoneally, and proposed that this ineffectiveness may have been the result of an insufficient dose of resveratrol. In another study, oral resveratrol at 100 or 200 mg/kg inhibited the development of 4T1 cells and metastasis in mouse lungs [252]. These findings were linked to both the reduced activity and expression of MMP-9. These data suggest that resveratrol’s effects on breast cancer hinge on the dose and route of administration.
With breast cancer cell–implanted fat-pad models employing cigarette smoke condensate–transformed MCF-10ATr cells [209] or SUM159 cells [253], resveratrol caused down-regulation of the expression of various proteins linked to survival and cell proliferation (cyclin D1, PI3K, PCNA, and β-catenin), proteins related to DNA repair (Fen-1, DNA-ligase-I, Pol-δ, and Pol-ε), and an anti-apoptotic protein (Bcl-xL). It also caused an up-regulation of the pro-apoptotic protein Bax and tumor-suppressor gene p21 in mouse mammary tissue [209,253]. When used to supplement drinking water, resveratrol delayed the growth of spontaneous mammary tumors in HER-2/neu transgenic mice, and lowered the mean size and number of mammary tumors by causing down-regulation of the HER-2/neu gene expression and raising apoptosis in the mammary glands of these mice [207].

9. Prostate Cancer

Dietary resveratrol considerably lowered the incidence of prostatic adenocarcinoma in the transgenic adenocarcinoma mouse prostate (TRAMP) model [216]. Resveratrol suppressed prostate cancer growth via down-regulating the androgen receptor (AR) expression in the TRAMP model of prostate cancer. Additionally, besides down-regulating the AR expression, resveratrol also suppressed the mRNA level of androgen-responsive glandular kallikrein 11, which has been determined to be an ortholog of the human prostate specific antigen (PSA) [217]. In a xenograft model, resveratrol delayed the development of AR-positive LNCaP tumors and inhibited the expression of steroid hormone response markers [254].
With the use of AR-negative PC-3 human prostate cancer–cell xenografts in the flank regions of mice, post-treatment with oral resveratrol (30 mg/kg/day) decreased the volume of tumors, with lowered tumor-cell proliferation and neovascularization, and induced apoptosis [214]. Intraperitoneal post-treatment with resveratrol (25 mg/kg/day) also decreased the tumor volume of PC-3 cell xenografts in mouse prostates [255]. Additionally, intraperitoneal post-treatment of resveratrol (50 mg/kg/day) in the orthotopic DU-145 prostate cancer model decreased the growth, progression, local invasion, and spontaneous metastasis of tumors [215].

10. Colorectal Cancer

Colorectal cancers arise due to several factors such as diet rich in red meat and processed meat and other lifestyle factors such as smoking and drinking alcohol [256],. Resveratrol’s in vivo effectiveness has been tested with colorectal cancer models employing genetically modified animals such as ApcPirc/+ rats and ApcMin/+ mice. Colon cancer can be induced by chemical carcinogens, which include azoxymethane (AOM), AOM plus dextran sulfate sodium (DSS), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-3-methylimidazo[4,5-f]quinoline, and 1,2-dimethylhydrazine (DMH) [257,258]. The pathophysiological and histopathological features/manifestations of colon cancer include aberrant crypt foci (ACF), hyperplasia, adenocarcinoma, and adenoma [258]. In models induced with AOM or AOM plus DSS, the oral administration (in the gavage or diet) of resveratrol decreased the incidence [259,260], individual size [224], and multiplicity [224,259,261] of ACF in rodent models, and triggered biomarker alterations.
Resveratrol augmented the expression of Bax [224], p53, and p-p53 at Ser15 [259], HO-1 [261], glutathione reductase (GR) [261], and Nrf2 [261], and reduced the expression of COX-2 [259,261], inducible nitric oxide synthase (iNOS) [259,261], TNF-α [259], aldose reductase [261], NF-κB [261], and p-protein kinase C-β2 (PKC-β2) [261]. It has been propounded that resveratrol down-regulates the aldose reductase–dependent activation of NF-κB and PKC-β2, with an ensuing lowering of the expression levels of COX-2 and iNOS [261]. In models induced with DMH, resveratrol decreased the incidence, [222] size [222,262], and multiplicity of ACF [222,262,263], as well as histopathological lesions [222] and DNA damage in leukocytes [264]. When used against colon carcinogenesis, the anti-tumor effects of resveratrol were found to be accompanied by alterations in the activities of enzymes. In rat models, the processes of anti-oxidant enzymes, including catalase (CAT) and SOD in the intestine/colon [262], liver [265], and erythrocytes [264], were augmented, and the processes of biotransforming enzymes, including β-glucosidase, β-glucuronidase, β-galactosidase, nitroreductase, and mucinase, in fresh fecal and colonic mucosal samples were reduced [222]. Resveratrol lowered the expression levels of ODC, COX-2, Mucin 1, cell surface associated (MUC1), heat-shock protein (Hsp)27, and Hsp70 in colonic mucosa [266], and increased the expression levels of caspase-3 in the colonic mucosa [266], and increased glutathione in the reduced state (GSH) in the liver, intestine/colon, plasma, and erythrocytes [262,264,265].
In models with genetically modified mice (e.g., ApcMin/+ mice [223,225,226]), and in mice with the APC locus knockout and activated KRAS [267], resveratrol supplementation inhibited the development of colon tumors [223,225,226,267,268] and occurrence of dysplasia [223].

11. Liver Cancer

The anti-cancer potential of resveratrol in liver carcinogenesis was exemplified by a decreased incidence and smaller numbers of nodules in models of animals employing chemical carcinogens [e.g., diethylnitrosamine (DENA) [269], DENA plus phenobarbital [234,270], and DENA plus 2-acetylaminofluorene (2-AAF) [271] or transgenic mice (e.g., hepatitis B virus X protein (HBx)-expressing transgenic mice) [272]. Additionally, resveratrol’s anti-tumor effects have been reported in xenograft models using hepatoma cell lines (e.g., H22, AH-130, HepG2, and AH109A) [227,228,229,232]. Dietary resveratrol completely prevented DENA-induced lipid peroxidation and enhanced protein carbonyl formation, which indicates that it may also attenuate oxidative stress in the liver. Resveratrol also elevated the expression of hepatic Nrf2 and reduced the expression of iNOS. That study reported that the attenuation of oxidative and nitrosative stress and the alleviation of the inflammatory response could be mediated through the transcriptional and translational regulation of Nrf2 signaling [273]. Recent studies with Nrf2-deficient mice have shown that Nrf2 plays a role in protecting the liver from xenobiotic-initiated hepatocarcinogenesis [274].
Rajasekaran et al. have studied resveratrol’s ability to prevent or treat hepatocellular carcinoma by administering resveratrol, starting at the time of DENA injection or for 15 days after the development of hepatocellular carcinoma [269]. Resveratrol treatment at both time points also reduced cell crowding and alteration in the cellular architecture, and decreased the liver size compared with control rats treated with DENA [269]. In the DENA-induced hepatocellular carcinoma model, administration of resveratrol inhibited the formation of hepatocyte nodules via down-regulating Hsp70 and COX-2 expression, through lowering the translocation of NF-κB from the cytoplasm to the nucleus [275]. Another study using the same administered dose of resveratrol also determined that the levels and expressions of hepatic TNF-α, IL-1β, and IL-6 induced by DENA can be reversed [276]. Resveratrol also exhibited a remarkable anti-angiogenic effect during the development of DENA-induced hepatocellular carcinogenesis, perhaps by blocking VEGF expression via the down-regulation of HIF-1α [277].
Resveratrol considerably lowered the cell count of a swiftly growing tumor (Yoshida AH-130 ascites hepatoma) injected into rats, thereby triggering apoptosis and cell accumulation in the G2/M phase [228]. It was further demonstrated that the inhibition of cell cycle progression involved reductions in the expression of p34cdc2 and cyclin B1 in murine transplantable liver tumors after resveratrol administration [230]. It has also been reported that resveratrol had anti-tumor-growth and anti-metastasis effects in Donryu rats that had an ascites AH109A hepatoma cell line subcutaneously implanted [227].
In another study, resveratrol inhibited tumor growth and angiogenesis in a hepatoma xenograft mouse model [278]. Salado et al. used B16 melanoma (B16M) cells to study the effects of resveratrol treatment on hepatic metastasis caused mainly by the production of pro-inflammatory cytokines [279]. Lin et al. investigated the effects of treatment with resveratrol on the precancerous stage of liver carcinogenesis in spontaneously induced hepatocellular carcinoma in HBx transgenic mice [272]. Resveratrol supplementation significantly reduced the incidence of hepatocellular carcinoma and increased the latency of tumor formation. Resveratrol inhibited hepatic lipogenesis and intracellular ROS, and the results from liver cancer models have been consistently positive, indicating the potential benefit of resveratrol in hepatocellular carcinoma prevention and/or therapy.

12. Pancreatic Cancer

Several lines of evidence suggests that age, being overweight, pancreatitis and family history of pancreatic cancer are the major risk factor for the development of pancreatic cancer. Within a xenograft mouse model, resveratrol delayed or suppressed the promotion of pancreatic cancer via inhibiting the activity of leukotriene A4 hydrolase (LTA4H), which stimulates the generation of pro-inflammatory cytokines and mediators [280], and also stimulates cancer cell proliferation [281,282]. Resveratrol blocked the tumor development of PANC-1 cells orthotopically implanted in nude mice, with augmented expression of apoptosis/cell cycle arrest proteins including Bim, p27, and cleaved caspase-3, and reduced cell survival/proliferation markers including PCNA expression and the phosphorylation of PI3K, ERK, Akt, FOXO3a (Ser253), and p-FOXO1 (Ser256) in tumor tissues [283]. Resveratrol treatment inhibited the formation and development of pancreatic cancer in KrasG12D transgenic mice that spontaneously develop pancreatic tumors [284]. However, dietary resveratrol had no anti-carcinogenic effect on BOP (N-nitrosobis(2-oxopropyl)amine)-induced pancreatic carcinogenesis in hamsters [285]. Further studies are necessary for additional preclinical evaluation of the efficacy of resveratrol in treating pancreatic cancer.

13. Lung Cancer

In preclinical models, lung carcinogenesis is known to be induced by a variety of agents, including diethylnitrosamine (DEN), nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), uracil mustard, vinyl carbamate, urethane, MNU, and BP [11]. In the BP-induced mouse lung carcinogenesis model, resveratrol treatment lowered the level of BP diolepoxide (BPDE)-DNA adducts [286], improved the ultrahistoarchitecture [287], and reduced the size of tumor nodules by increasing pulmonary caspase-3 and -9 activity. It also abrogated glucose uptake/turnover, reduced the serum lactate dehydrogenase (LDH) activity (which is heightened in cancer cells), and lowered the p-p53 levels at Ser15 (the hyperphosphorylation of which can result in the inactivation of p53) [288]. In Lewis lung carcinoma cell xenograft models, treatment with resveratrol reduced the growth of tumors [218,221]. It has been also discovered that treatment with resveratrol reduced the development of A549 and MSTO-211H xenografts in mice [219,289,290].
Resveratrol’s anti-tumor effects in A549 xenografts were reduced in Forkhead box protein C2 (FOXC2)-overexpressing A549 xenografts, which suggests that resveratrol possibly induces anti-tumor activity through FOXC2 [289]. Another study discovered that resveratrol did not affect the development of Lewis lung carcinoma implanted in mice, but demonstrated an evident anti-metastatic effect, decreasing both the weight and number of lung metastases [220]. However, resveratrol used to supplement the diet did not affect lung tumor multiplicity in BP plus NNK-induced lung carcinogenesis in A/J mice [291]. Similarly, in BP-induced lung carcinogenesis, resveratrol did not cause a change in the expression levels of BP-metabolizing genes (such as CYP1A1 and CYP1B1) and the number of B[a]P-protein adducts in lung tissues [292]. Another study found that both the natural Egr-1 promoter and the synthetic promoter triggered the expression of GADD45α when used with resveratrol, and then suppressed the proliferation of A549 lung cancer cells and induced apoptosis [293].

14. Other Cancers

Resveratrol provides considerable protection against the induction of cancer within the oral cavity [294] and the esophagus [295], among other tissues. Its cancer chemopreventive activity aside, resveratrol can also inhibit the development and/or induce the regression of established tumors in xenograft models for cancers of the ovaries [296], urinary bladder [79], stomach [297], and head and neck [298,299]. Resveratrol treatment effectively suppressed the growth rate of and augmented apoptosis in neuroblastoma; this was accompanied by the up-regulation of cyclin E and the down-regulation of p21 [300]. It has recently been demonstrated that resveratrol considerably reduced tumor growth via inducing apoptosis, which involved direct activation of the mitochondrial intrinsic apoptotic pathway in the NGP and SK-N-AS xenograft models of human neuroblastoma [301]. Resveratrol caused significant inhibition of cerebral tumors through inducing apoptosis and inhibiting angiogenesis induced by glioma [302]. Rats that had undergone resveratrol treatment had lower growth rates of glioma, which correlated with the blood flow of tumors (signified by the color Doppler vascularity index) and density of microvessels.
Resveratrol’s anti-angiogenic effect has caused researchers to investigate if it could inhibit the development of a murine fibrosarcoma; water supplemented with resveratrol indeed significantly inhibited the development of T241fibrosarcoma in mice via suppressing angiogenesis [303]. Resveratrol’s in vivo anti-cancer effects were studied in N-nitrosomethyl-benzylamine (NMBA)-induced esophageal tumorigenesis in rats. Resveratrol suppressed both the size and number of NMBA-induced esophageal tumors per rat through targeting prostaglandin E2 and COXs [304]. In a gastric cancer xenograft nude mouse model, resveratrol inhibited the growth of tumors, with reductions in the expression of cyclin D1, Ki67, CDK4, and CDK6, and increases in the expression of p16, p21, and β-Gal [305]. Resveratrol considerably inhibited carcinoma development when it was injected in close proximity to the carcinoma in a tumor model created by transplanting human primary gastric cancer cells into the subcutaneous tissue of nude mice [297]. Resveratrol induced apoptosis in implanted tumor cells via down-regulation of the apoptosis-regulated gene Bcl-2 and up-regulation of the apoptosis-regulated gene Bax. For the anti-tumor effects in head and neck cancer, resveratrol suppressed tumor stemness via lowering the expression of mesenchymal-like protein (Vimentin) and stemness markers (Oct4 and Nestin), inducing epithelial protein expression (E-cadherin) [299], and increasing γ-histone 2AX (a DNA damage marker) and cleaved caspase-3 expression [298]. In an ovarian cancer model, resveratrol abrogated the development of NuTu-19 ovarian cancer cells in vitro. However, in vivo, when NuTu-19 cells were injected into the ovarian bursa of rats and the rats were fed with resveratrol (100 mg/kg) mixed in their diet for 28 days, the growth of the ovarian tumors was not significantly inhibited [306].

15. Clinical Trials with Resveratrol

Although it is clear that resveratrol has shown excellent anti-cancer properties, most of the studies were performed in cell-culture and pre-clinical models. These physiological effects of resveratrol were also investigated in humans because it cannot be assumed that the results of tests in animal models will hold true for humans, because of differences in genetics and metabolism profile. The pharmacokinetics, metabolism, and toxicity of resveratrol have been assessed in healthy volunteers and cancer patients [307,308,309]. Resveratrol is metabolized swiftly, mainly into glucuronide and sulfate conjugates that are excreted via the urine. Because of the poor bioavailability of resveratrol due to its extensive metabolism, large doses (up to a maximum of 5 g/day) have been utilized by researchers. These studies have shown that resveratrol seems to be well tolerated and safe. However, adverse effects including diarrhea, nausea, and abdominal pain were observed in subjects taking more than 1 g of resveratrol daily [307]. Subsequent clinical trials are currently investigating this dose limit [307,310]. Resveratrol’s poor bioavailability is a significant issue with regard to extrapolating its effects to humans, and various approaches have been created to enhance its bioavailability [311], including consuming it with various foods [312], using it in combination with an additional phytochemical piperine [313], and using a prodrug approach [314], micronized powders [315,316], or nanotechnological formulations [317,318,319].
The effect of resveratrol in cancer patients has been investigated in a few clinical trials (Table 2). The first clinical trial dealing with resveratrol and cancer was performed by Nguyen et al. [320]. They examined the effects of freeze-dried grape powder (GP) (containing resveratrol and resveratrol derived from plants) on the Wnt signaling pathway, which is known to be involved in colon carcinogenesis [321], in regular colon cancer and colonic mucosa. GP administration (80 g/day containing 0.07 mg of resveratrol) for two weeks resulted in decreased Wnt target gene expression within regular mucosa, but had no effect on cancerous mucosa. This indicates that GP or resveratrol may play a beneficial part in the prevention of colon cancer, rather than in the treatment of established colon cancer. Patel et al. studied the effects of the administration of resveratrol at 0.5 or 1 g/day for eight days on proliferation marker Ki-67 expression in colorectal tissue, and reported a 5% decrease in the proliferation of tumor cells [322]. In colorectal cancer patients with hepatic metastasis, SRT501 (a micronized resveratrol formulation manufactured by Sirtris Pharmaceuticals, a GSK Company, Cambridge, MA, USA) supplementation at 5 g/day for two weeks increased the amount of cleaved caspase-3 within hepatic tissue, which suggests that there was increased apoptosis of cancerous tissue compared with subjects treated with a placebo [315].
In a muscadine grape skin extract phase 1 study with biochemically recurrent prostate cancer patients who were assigned to a high dose (4000 mg/patient) of pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol was found to be safe and warrants further investigation in dose-evaluating phase II trial [323]. In another randomized placebo controlled clinical study using two doses of resveratrol (150 mg or 1000 mg resveratrol daily) for 4 months was found to significantly lowered serum levels of androstenedione, dehydroepiandrosterone and dehydroepiandrosterone-sulphate, whereas prostate size was unaffected in benign prostate hyperplasia patients [324].
Primary protein carbonylation has been found to be increased several folds in presence of high levels of reactive oxygen species (ROS) such as superoxide anion free radical (O2) and nitric oxide free radical (NO) and other reactive free radicals, such as hydrogen peroxide (H2O2), hydroxyl radical (HO), and peroxynitrite anion (ONOO). There are several sources of ROS in the digestive tract and several microbes present in the colon produce a large amount of ROS inside the cells are by products of mitochondrial respiration in aerobic metabolism, and in chronic inflammation, a large amount of ROS is produced by neutrophil phagocytosis of bacteria, granular materials, or soluble irritants [325,326]. The oxidative decomposition of polyunsaturated fatty acids can initiate chain reactions that lead to the formation of a variety of carbonyl species (three to nine carbons in length), the most reactive and cytotoxic being α,β-unsaturated aldehydes also referred to as electrophilic carbonyls. These include acrolein, glyoxal, methylglyoxal, crotonaldehyde, malondialdehyde, and 4-hydroxynonenal. Reactive ketones or aldehydes that can be reacted by 2,4-dinitrophenylhydrazine (DNPH) to form 2,4-dinitrophenylhydrazone (DNP). Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease (IBD) in which oxidative stress plays a critical role in its pathogenesis and malignant progression to colorectal cancer (CRC) [327,328]. Oxidative activation of transcription factors NF-κB stimulates expression of a variety of pro-inflammatory cytokines in the intestinal epithelial cells, such as TNF-α, IL-1, IL-8, and COX-2, and promotes inflammation and carcinogenesis. Oxidative stress also activates mitogen-activated protein (MAP) kinase (MAPK) signaling pathways. The human gastrointestinal tract is exposed to carbonyl threats such as consumption red meat, alcoholic beverages and smoking increases protein carbonylation, inflammation and initiation of tumor development. However, dietary intake of green leafy vegetables, fruits, fish and wine has shown to decrease protein carbonylation [329]. It has also been reported that resveratrol supplementation at 5 mg/day for six days increased the degree of protein carbonyl concentrations and cytoprotective enzyme NQO1 in colorectal mucosa tissues from patients with colorectal cancer, compared with their control subjects [330]. However, contrary to these positive findings, some evidence that resveratrol supplementation may have adverse effects in certain cancer patients also exist. In a phase II clinical trial involving multiple myeloma patients, SRT501 supplementation at 5 g/day caused several unexpected adverse effects, including nephrotoxicity, which may have led to the death of one patient [316]. However, this high dose of SRT501 was determined to be safe in other clinical trials involving several healthy and diseased populations [315,316]. There are very low amounts of human data regarding the efficacy of resveratrol in cancer treatment. Since most of these clinical trials have had a small patient sample size and used different doses and different routes of resveratrol, the data from human clinical studies have shown inconsistent outcomes of resveratrol administration.
In addition to the effects in subjects with cancer, the effect of resveratrol in subjects with a higher cancer risk has also been demonstrated. For instance, resveratrol supplementation at 50 mg two times per day for 12 weeks reduced the DNA methylation of the tumor-suppressor gene Ras association domain-containing protein 1 (RASSF1A) in the breasts of women with higher risk of breast cancer [331]. It has also been shown that resveratrol supplementation at 1 g/day for 12 weeks increases the concentrations of sex steroid hormone binding globulin (SHBG), which has been linked to a reduction in the risk of breast cancer [332], and has favorable effects on estrogen metabolism; thus, it can lower risk factors for breast cancer in obese and overweight postmenopausal women [333]. Another clinical study concentrated on resveratrol’s effects on potential biomarkers for cancer risk reduction. Circulating concentrations of insulin-like growth factor (IGF-1) and IGF-binding protein 3 (IGFBP-3) are linked to a higher risk of common cancers [334]. Brown et al. showed that resveratrol administration at 2.5 g/day for 29 days resulted in a reduction of the circulating levels of IGF-1 and IGFBP-3 in healthy volunteers [335]. Their research suggests that resveratrol’s ability to decrease circulating IGF-1 and IGFBP-3 in humans may constitute an anti-carcinogenic mechanism. In another study, Chow et al. found that resveratrol administration at 1 g/day for four weeks modulated phase I isoenzymes (cytochrome P450) and phase II detoxification enzymes involved in carcinogen activation and detoxification [310]. However, these beneficial effects are mostly minimal and sometimes controversial. Nevertheless, it seems that resveratrol has had some beneficial effects with regard to the prevention and treatment of cancer. Therefore, the efficacy and safety of resveratrol in human trials must be further investigated to better understand and develop its therapeutic potential for cancer patients.

16. Conclusions and Future Perspectives

Using a variety of in vivo and in vitro models, it has been proven that resveratrol is capable of attenuating the various stages of carcinogenesis, some of which are briefly described in Figure 2. A vast body of experimental in vivo and in vitro studies and a few clinical trials has presented evidence of resveratrol’s great potential as an anti-cancer agent, both for the prevention and therapy of a large range of cancers. Resveratrol has a very low toxicity, and, although it has multiple molecular targets, it acts on different protective and common pathways that are usually altered in a great number of tumors. This suggests that resveratrol may be more suitable for use as an anti-carcinogen and it can also effectively exert it antineoplastic effects in conjunction with diverse chemotherapeutics and targeted therapies. The ability to prevent carcinogenesis includes the inhibition of oxidative stress, inflammation, and cancer-cell proliferation, and the activation of tightly regulated cell-death mechanisms. Due to the complexity and number of cellular processes involved, however, more studies must be performed to completely understand how resveratrol could be used to prevent the development of cancer. Moreover, resveratrol’s poor bioavailability in humans has been a critical concern with regard to the translation of basic research findings to the development of therapeutic agents. Although human clinical trials have produced positive findings, many conflicting results remain, which may be partly because of the dosing protocols employed. To augment resveratrol’s bioavailability and as a potential adjuvant, active research should be focused on resveratrol delivery systems, formulations, and modulation of resveratrol metabolism, and resveratrol’s possible interactions with other compounds, as well as the development of more bioavailable analogs of the compound.

Acknowledgments

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (NRF-2015R1A4A1042399 and NRF-2016R1A6A3A11930941).

Author Contributions

Jeong-Hyeon Ko, Jae-Young Um and Muthu K Shanmugam designed and wrote the manuscript; Frank Arfuso, Alan Prem Kumar, Anupam Bishayee, Gautam Sethi, and Kwang Seok Ahn edited and finalized the manuscript for submission.

Conflicts of Interest

The authors declare no competing financial interests.

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 2017, 67, 7–30. [Google Scholar] [CrossRef] [PubMed]
  2. Okimoto, R.A.; Bivona, T.G. Recent advances in personalized lung cancer medicine. Pers. Med. 2014, 11, 309–321. [Google Scholar] [CrossRef]
  3. Krepler, C.; Xiao, M.; Sproesser, K.; Brafford, P.A.; Shannan, B.; Beqiri, M.; Liu, Q.; Xu, W.; Garman, B.; Nathanson, K.L.; et al. Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin. Cancer Res. 2016, 22, 1592–1602. [Google Scholar] [CrossRef] [PubMed]
  4. Hong, W.K.; Sporn, M.B. Recent advances in chemoprevention of cancer. Science 1997, 278, 1073–1077. [Google Scholar] [CrossRef] [PubMed]
  5. Sethi, G.; Shanmugam, M.K.; Ramachandran, L.; Kumar, A.P.; Tergaonkar, V. Multifaceted link between cancer and inflammation. Biosci. Rep. 2012, 32, 1–15. [Google Scholar] [CrossRef] [PubMed]
  6. Chai, E.Z.; Siveen, K.S.; Shanmugam, M.K.; Arfuso, F.; Sethi, G. Analysis of the intricate relationship between chronic inflammation and cancer. Biochem. J. 2015, 468, 1–15. [Google Scholar] [CrossRef] [PubMed]
  7. Sethi, G.; Tergaonkar, V. Potential pharmacological control of the NF-κB pathway. Trends Pharmacol. Sci. 2009, 30, 313–321. [Google Scholar] [CrossRef] [PubMed]
  8. Janakiram, N.B.; Mohammed, A.; Madka, V.; Kumar, G.; Rao, C.V. Prevention and treatment of cancers by immune modulating nutrients. Mol. Nutr. Food Res. 2016, 60, 1275–1294. [Google Scholar] [CrossRef] [PubMed]
  9. Shanmugam, M.K.; Kannaiyan, R.; Sethi, G. Targeting cell signaling and apoptotic pathways by dietary agents: Role in the prevention and treatment of cancer. Nutr. Cancer 2011, 63, 161–173. [Google Scholar] [CrossRef] [PubMed]
  10. Aggarwal, B.B.; Van Kuiken, M.E.; Iyer, L.H.; Harikumar, K.B.; Sung, B. Molecular targets of nutraceuticals derived from dietary spices: Potential role in suppression of inflammation and tumorigenesis. Exp. Biol. Med. 2009, 234, 825–849. [Google Scholar] [CrossRef] [PubMed]
  11. Aggarwal, B.B.; Vijayalekshmi, R.V.; Sung, B. Targeting inflammatory pathways for prevention and therapy of cancer: Short-term friend, long-term foe. Clin. Cancer Res. 2009, 15, 425–430. [Google Scholar] [CrossRef] [PubMed]
  12. Yang, S.F.; Weng, C.J.; Sethi, G.; Hu, D.N. Natural bioactives and phytochemicals serve in cancer treatment and prevention. Evid.-Based Complement. Altern. Med. 2013, 2013, 698190. [Google Scholar] [CrossRef] [PubMed]
  13. Tang, C.H.; Sethi, G.; Kuo, P.L. Novel medicines and strategies in cancer treatment and prevention. BioMed Res. Int. 2014, 2014, 474078. [Google Scholar] [CrossRef] [PubMed]
  14. Shanmugam, M.K.; Rane, G.; Kanchi, M.M.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Tan, B.K.; Kumar, A.P.; Sethi, G. The multifaceted role of curcumin in cancer prevention and treatment. Molecules 2015, 20, 2728–2769. [Google Scholar] [CrossRef] [PubMed]
  15. Kannaiyan, R.; Shanmugam, M.K.; Sethi, G. Molecular targets of celastrol derived from Thunder of God Vine: Potential role in the treatment of inflammatory disorders and cancer. Cancer Lett. 2011, 303, 9–20. [Google Scholar] [CrossRef] [PubMed]
  16. Hsieh, Y.S.; Yang, S.F.; Sethi, G.; Hu, D.N. Natural bioactives in cancer treatment and prevention. BioMed Res. Int. 2015, 2015, 182835. [Google Scholar] [CrossRef] [PubMed]
  17. Bishayee, A.; Sethi, G. Bioactive natural products in cancer prevention and therapy: Progress and promise. Semin. Cancer Biol. 2016, 40–41, 1–3. [Google Scholar] [CrossRef] [PubMed]
  18. Shrimali, D.; Shanmugam, M.K.; Kumar, A.P.; Zhang, J.; Tan, B.K.; Ahn, K.S.; Sethi, G. Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer. Cancer Lett. 2013, 341, 139–149. [Google Scholar] [CrossRef] [PubMed]
  19. Shanmugam, M.K.; Nguyen, A.H.; Kumar, A.P.; Tan, B.K.; Sethi, G. Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer. Cancer Lett. 2012, 320, 158–170. [Google Scholar] [CrossRef] [PubMed]
  20. Shanmugam, M.K.; Lee, J.H.; Chai, E.Z.; Kanchi, M.M.; Kar, S.; Arfuso, F.; Dharmarajan, A.; Kumar, A.P.; Ramar, P.S.; Looi, C.Y.; et al. Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds. Semin. Cancer Biol. 2016, 40–41, 35–47. [Google Scholar] [CrossRef] [PubMed]
  21. Shanmugam, M.K.; Arfuso, F.; Kumar, A.P.; Wang, L.; Goh, B.C.; Ahn, K.S.; Bishayee, A.; Sethi, G. Modulation of diverse oncogenic transcription factors by thymoquinone, an essential oil compound isolated from the seeds of Nigella sativa Linn. Pharmacol. Res. 2017. [Google Scholar] [CrossRef] [PubMed]
  22. Prasannan, R.; Kalesh, K.A.; Shanmugam, M.K.; Nachiyappan, A.; Ramachandran, L.; Nguyen, A.H.; Kumar, A.P.; Lakshmanan, M.; Ahn, K.S.; Sethi, G. Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer. Biochem. Pharmacol. 2012, 84, 1268–1276. [Google Scholar] [CrossRef] [PubMed]
  23. Shanmugam, M.K.; Warrier, S.; Kumar, A.P.; Sethi, G.; Arfuso, F. Potential role of natural compounds as anti-angiogenic agents in cancer. Curr. Vasc. Pharmacol. 2017, 15, 503–519. [Google Scholar] [CrossRef] [PubMed]
  24. Newman, D.J.; Cragg, G.M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629–661. [Google Scholar] [CrossRef] [PubMed]
  25. Aggarwal, B.B.; Bhardwaj, A.; Aggarwal, R.S.; Seeram, N.P.; Shishodia, S.; Takada, Y. Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. Anticancer Res. 2004, 24, 2783–2840. [Google Scholar] [PubMed]
  26. Bishayee, A. Cancer prevention and treatment with resveratrol: From rodent studies to clinical trials. Cancer Prev. Res. 2009, 2, 409–418. [Google Scholar] [CrossRef] [PubMed]
  27. Bishayee, A.; Politis, T.; Darvesh, A.S. Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma. Cancer Treat. Rev. 2010, 36, 43–53. [Google Scholar] [CrossRef] [PubMed]
  28. Sinha, D.; Sarkar, N.; Biswas, J.; Bishayee, A. Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms. Semin. Cancer Boil. 2016, 40–41, 209–232. [Google Scholar] [CrossRef] [PubMed]
  29. Cucciolla, V.; Borriello, A.; Oliva, A.; Galletti, P.; Zappia, V.; Della Ragione, F. Resveratrol: From basic science to the clinic. Cell Cycle 2007, 6, 2495–2510. [Google Scholar] [CrossRef] [PubMed]
  30. Soleas, G.J.; Diamandis, E.P.; Goldberg, D.M. Resveratrol: A molecule whose time has come? And gone? Clin. Biochem. 1997, 30, 91–113. [Google Scholar] [CrossRef]
  31. Jeandet, P.; Douillet-Breuil, A.C.; Bessis, R.; Debord, S.; Sbaghi, M.; Adrian, M. Phytoalexins from the Vitaceae: Biosynthesis, phytoalexin gene expression in transgenic plants, antifungal activity, and metabolism. J. Agric. Food Chem. 2002, 50, 2731–2741. [Google Scholar] [CrossRef] [PubMed]
  32. Cai, Y.J.; Wei, Q.Y.; Fang, J.G.; Yang, L.; Liu, Z.L.; Wyche, J.H.; Han, Z. The 3,4-dihydroxyl groups are important for trans-resveratrol analogs to exhibit enhanced antioxidant and apoptotic activities. Anticancer Res. 2004, 24, 999–1002. [Google Scholar] [PubMed]
  33. Colin, D.; Lancon, A.; Delmas, D.; Lizard, G.; Abrossinow, J.; Kahn, E.; Jannin, B.; Latruffe, N. Antiproliferative activities of resveratrol and related compounds in human hepatocyte derived HepG2 cells are associated with biochemical cell disturbance revealed by fluorescence analyses. Biochimie 2008, 90, 1674–1684. [Google Scholar] [CrossRef] [PubMed]
  34. Moran, B.W.; Anderson, F.P.; Devery, A.; Cloonan, S.; Butler, W.E.; Varughese, S.; Draper, S.M.; Kenny, P.T. Synthesis, structural characterisation and biological evaluation of fluorinated analogues of resveratrol. Bioorg. Med. Chem. 2009, 17, 4510–4522. [Google Scholar] [CrossRef] [PubMed]
  35. Mondal, A.; Bennett, L.L. Resveratrol enhances the efficacy of sorafenib mediated apoptosis in human breast cancer MCF7 cells through ROS, cell cycle inhibition, caspase 3 and PARP cleavage. Biomed. Pharmacother. 2016, 84, 1906–1914. [Google Scholar] [CrossRef] [PubMed]
  36. Lee, Y.J.; Lee, G.J.; Yi, S.S.; Heo, S.H.; Park, C.R.; Nam, H.S.; Cho, M.K.; Lee, S.H. Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells. Food Chem. Toxicol. 2016, 97, 96–107. [Google Scholar] [CrossRef] [PubMed]
  37. Stagos, D.; Amoutzias, G.D.; Matakos, A.; Spyrou, A.; Tsatsakis, A.M.; Kouretas, D. Chemoprevention of liver cancer by plant polyphenols. Food Chem. Toxicol. 2012, 50, 2155–2170. [Google Scholar] [CrossRef] [PubMed]
  38. Carter, L.G.; D’Orazio, J.A.; Pearson, K.J. Resveratrol and cancer: Focus on in vivo evidence. Endocr. Relat. Cancer 2014, 21, R209–R225. [Google Scholar] [CrossRef] [PubMed]
  39. Stagos, D.; Portesis, N.; Spanou, C.; Mossialos, D.; Aligiannis, N.; Chaita, E.; Panagoulis, C.; Reri, E.; Skaltsounis, L.; Tsatsakis, A.M.; et al. Correlation of total polyphenolic content with antioxidant and antibacterial activity of 24 extracts from Greek domestic Lamiaceae species. Food Chem. Toxicol. 2012, 50, 4115–4124. [Google Scholar] [CrossRef] [PubMed]
  40. Mazzanti, G.; Di Giacomo, S. Curcumin and Resveratrol in the Management of Cognitive Disorders: What is the Clinical Evidence? Molecules 2016, 21, 1243. [Google Scholar] [CrossRef] [PubMed]
  41. Molino, S.; Dossena, M.; Buonocore, D.; Ferrari, F.; Venturini, L.; Ricevuti, G.; Verri, M. Polyphenols in dementia: From molecular basis to clinical trials. Life Sci. 2016, 161, 69–77. [Google Scholar] [CrossRef] [PubMed]
  42. Wadsworth, T.L.; Koop, D.R. Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages. Biochem. Pharmacol. 1999, 57, 941–949. [Google Scholar] [CrossRef]
  43. Ray, P.S.; Maulik, G.; Cordis, G.A.; Bertelli, A.A.; Bertelli, A.; Das, D.K. The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic. Boil. Med. 1999, 27, 160–169. [Google Scholar] [CrossRef]
  44. Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; Lopez-Lluch, G.; Lewis, K.; et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444, 337–342. [Google Scholar] [CrossRef] [PubMed]
  45. Renaud, S.; de Lorgeril, M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992, 339, 1523–1526. [Google Scholar] [CrossRef]
  46. Jang, M.; Cai, L.; Udeani, G.O.; Slowing, K.V.; Thomas, C.F.; Beecher, C.W.; Fong, H.H.; Farnsworth, N.R.; Kinghorn, A.D.; Mehta, R.G.; et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997, 275, 218–220. [Google Scholar] [CrossRef] [PubMed]
  47. Tome-Carneiro, J.; Larrosa, M.; Gonzalez-Sarrias, A.; Tomas-Barberan, F.A.; Garcia-Conesa, M.T.; Espin, J.C. Resveratrol and clinical trials: The crossroad from in vitro studies to human evidence. Curr. Pharm. Des. 2013, 19, 6064–6093. [Google Scholar] [CrossRef] [PubMed]
  48. Kundu, J.K.; Surh, Y.J. Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives. Cancer Lett. 2008, 269, 243–261. [Google Scholar] [CrossRef] [PubMed]
  49. Harikumar, K.B.; Kunnumakkara, A.B.; Sethi, G.; Diagaradjane, P.; Anand, P.; Pandey, M.K.; Gelovani, J.; Krishnan, S.; Guha, S.; Aggarwal, B.B. Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer. Int. J. Cancer 2010, 127, 257–268. [Google Scholar] [PubMed]
  50. Minamoto, T.; Mai, M.; Ronai, Z. Environmental factors as regulators and effectors of multistep carcinogenesis. Carcinogenesis 1999, 20, 519–527. [Google Scholar] [CrossRef] [PubMed]
  51. Khansari, N.; Shakiba, Y.; Mahmoudi, M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat. Inflamm. Allergy Drug Discov. 2009, 3, 73–80. [Google Scholar] [CrossRef] [PubMed]
  52. Barzilai, A.; Yamamoto, K. DNA damage responses to oxidative stress. DNA Repair 2004, 3, 1109–1115. [Google Scholar] [CrossRef] [PubMed]
  53. Fruehauf, J.P.; Meyskens, F.L., Jr. Reactive oxygen species: A breath of life or death? Clin. Cancer Res. 2007, 13, 789–794. [Google Scholar] [CrossRef] [PubMed]
  54. Windmill, K.F.; McKinnon, R.A.; Zhu, X.; Gaedigk, A.; Grant, D.M.; McManus, M.E. The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: Functional and localization studies. Mutat. Res. 1997, 376, 153–160. [Google Scholar] [CrossRef]
  55. Galati, G.; Teng, S.; Moridani, M.Y.; Chan, T.S.; O’Brien, P.J. Cancer chemoprevention and apoptosis mechanisms induced by dietary polyphenolics. Drug Metab. Drug Interact. 2000, 17, 311–349. [Google Scholar] [CrossRef]
  56. Guengerich, F.P. Metabolism of chemical carcinogens. Carcinogenesis 2000, 21, 345–351. [Google Scholar] [CrossRef] [PubMed]
  57. Sharma, S.; Stutzman, J.D.; Kelloff, G.J.; Steele, V.E. Screening of potential chemopreventive agents using biochemical markers of carcinogenesis. Cancer Res. 1994, 54, 5848–5855. [Google Scholar] [PubMed]
  58. Martinez, J.; Moreno, J.J. Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem. Pharmacol. 2000, 59, 865–870. [Google Scholar] [CrossRef]
  59. Leonard, S.S.; Xia, C.; Jiang, B.H.; Stinefelt, B.; Klandorf, H.; Harris, G.K.; Shi, X. Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem. Biophys. Res. Commun. 2003, 309, 1017–1026. [Google Scholar] [CrossRef] [PubMed]
  60. Kim, H.J.; Chang, E.J.; Bae, S.J.; Shim, S.M.; Park, H.D.; Rhee, C.H.; Park, J.H.; Choi, S.W. Cytotoxic and antimutagenic stilbenes from seeds of Paeonia lactiflora. Arch. Pharm. Res. 2002, 25, 293–299. [Google Scholar] [CrossRef] [PubMed]
  61. Sgambato, A.; Ardito, R.; Faraglia, B.; Boninsegna, A.; Wolf, F.I.; Cittadini, A. Resveratrol, a natural phenolic compound, inhibits cell proliferation and prevents oxidative DNA damage. Mutat. Res. 2001, 496, 171–180. [Google Scholar] [CrossRef]
  62. Attia, S.M. Influence of resveratrol on oxidative damage in genomic DNA and apoptosis induced by cisplatin. Mutat. Res. 2012, 741, 22–31. [Google Scholar] [CrossRef] [PubMed]
  63. Chen, Z.H.; Hurh, Y.J.; Na, H.K.; Kim, J.H.; Chun, Y.J.; Kim, D.H.; Kang, K.S.; Cho, M.H.; Surh, Y.J. Resveratrol inhibits TCDD-induced expression of CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells. Carcinogenesis 2004, 25, 2005–2013. [Google Scholar] [CrossRef] [PubMed]
  64. Ciolino, H.P.; Yeh, G.C. Inhibition of aryl hydrocarbon-induced cytochrome P-450 1A1 enzyme activity and CYP1A1 expression by resveratrol. Mol. Pharmacol. 1999, 56, 760–767. [Google Scholar] [PubMed]
  65. Beedanagari, S.R.; Bebenek, I.; Bui, P.; Hankinson, O. Resveratrol inhibits dioxin-induced expression of human CYP1A1 and CYP1B1 by inhibiting recruitment of the aryl hydrocarbon receptor complex and RNA polymerase II to the regulatory regions of the corresponding genes. Toxicol. Sci. 2009, 110, 61–67. [Google Scholar] [CrossRef] [PubMed]
  66. Peng, T.L.; Chen, J.; Mao, W.; Song, X.; Chen, M.H. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. BMC Cell Boil. 2009, 10, 27. [Google Scholar] [CrossRef] [PubMed]
  67. Hsieh, T.C.; Lu, X.; Wang, Z.; Wu, J.M. Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of transcription factor Nrf2. Med. Chem. 2006, 2, 275–285. [Google Scholar] [PubMed]
  68. Heo, Y.H.; Kim, S.; Park, J.E.; Jeong, L.S.; Lee, S.K. Induction of quinone reductase activity by stilbene analogs in mouse Hepa 1c1c7 cells. Arch. Pharm. Res. 2001, 24, 597–600. [Google Scholar] [CrossRef] [PubMed]
  69. Bianco, N.R.; Chaplin, L.J.; Montano, M.M. Differential induction of quinone reductase by phytoestrogens and protection against oestrogen-induced DNA damage. Biochem. J. 2005, 385, 279–287. [Google Scholar] [CrossRef] [PubMed]
  70. Lee, J.S.; Surh, Y.J. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett. 2005, 224, 171–184. [Google Scholar] [CrossRef] [PubMed]
  71. Kensler, T.W.; Wakabayashi, N. Nrf2: Friend or foe for chemoprevention? Carcinogenesis 2010, 31, 90–99. [Google Scholar] [CrossRef] [PubMed]
  72. Lu, F.; Zahid, M.; Wang, C.; Saeed, M.; Cavalieri, E.L.; Rogan, E.G. Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev. Res. 2008, 1, 135–145. [Google Scholar] [CrossRef] [PubMed]
  73. Zahid, M.; Gaikwad, N.W.; Ali, M.F.; Lu, F.; Saeed, M.; Yang, L.; Rogan, E.G.; Cavalieri, E.L. Prevention of estrogen-DNA adduct formation in MCF-10F cells by resveratrol. Free Radic. Boil. Med. 2008, 45, 136–145. [Google Scholar] [CrossRef] [PubMed]
  74. Zhang, H.; Shih, A.; Rinna, A.; Forman, H.J. Exacerbation of tobacco smoke mediated apoptosis by resveratrol: An unexpected consequence of its antioxidant action. Int. J. Biochem. Cell Boil. 2011, 43, 1059–1064. [Google Scholar] [CrossRef] [PubMed]
  75. Kode, A.; Rajendrasozhan, S.; Caito, S.; Yang, S.R.; Megson, I.L.; Rahman, I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2008, 294, L478–L488. [Google Scholar] [CrossRef] [PubMed]
  76. Klaunig, J.E.; Kamendulis, L.M. The role of oxidative stress in carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 2004, 44, 239–267. [Google Scholar] [CrossRef] [PubMed]
  77. Wolter, F.; Akoglu, B.; Clausnitzer, A.; Stein, J. Downregulation of the cyclin D1/Cdk4 complex occurs during resveratrol-induced cell cycle arrest in colon cancer cell lines. J. Nutr. 2001, 131, 2197–2203. [Google Scholar] [PubMed]
  78. Benitez, D.A.; Pozo-Guisado, E.; Alvarez-Barrientos, A.; Fernandez-Salguero, P.M.; Castellon, E.A. Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines. J. Androl. 2007, 28, 282–293. [Google Scholar] [CrossRef] [PubMed]
  79. Bai, Y.; Mao, Q.Q.; Qin, J.; Zheng, X.Y.; Wang, Y.B.; Yang, K.; Shen, H.F.; Xie, L.P. Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo. Cancer Sci. 2010, 101, 488–493. [Google Scholar] [CrossRef] [PubMed]
  80. Gatouillat, G.; Balasse, E.; Joseph-Pietras, D.; Morjani, H.; Madoulet, C. Resveratrol induces cell-cycle disruption and apoptosis in chemoresistant B16 melanoma. J. Cell. Biochem. 2010, 110, 893–902. [Google Scholar] [CrossRef] [PubMed]
  81. Ferry-Dumazet, H.; Garnier, O.; Mamani-Matsuda, M.; Vercauteren, J.; Belloc, F.; Billiard, C.; Dupouy, M.; Thiolat, D.; Kolb, J.P.; Marit, G.; et al. Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells. Carcinogenesis 2002, 23, 1327–1333. [Google Scholar] [CrossRef] [PubMed]
  82. Filippi-Chiela, E.C.; Villodre, E.S.; Zamin, L.L.; Lenz, G. Autophagy interplay with apoptosis and cell cycle regulation in the growth inhibiting effect of resveratrol in glioma cells. PLoS ONE 2011, 6, e20849. [Google Scholar] [CrossRef] [PubMed]
  83. Liao, P.C.; Ng, L.T.; Lin, L.T.; Richardson, C.D.; Wang, G.H.; Lin, C.C. Resveratrol arrests cell cycle and induces apoptosis in human hepatocellular carcinoma Huh-7 cells. J. Med. Food 2010, 13, 1415–1423. [Google Scholar] [CrossRef] [PubMed]
  84. Rashid, A.; Liu, C.; Sanli, T.; Tsiani, E.; Singh, G.; Bristow, R.G.; Dayes, I.; Lukka, H.; Wright, J.; Tsakiridis, T. Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways. Radiat. Oncol. 2011, 6, 144. [Google Scholar] [CrossRef] [PubMed]
  85. Hsieh, T.C.; Wong, C.; John Bennett, D.; Wu, J.M. Regulation of p53 and cell proliferation by resveratrol and its derivatives in breast cancer cells: An in silico and biochemical approach targeting integrin αvβ3. Int. J. Cancer 2011, 129, 2732–2743. [Google Scholar] [CrossRef] [PubMed]
  86. Farnebo, M.; Bykov, V.J.; Wiman, K.G. The p53 tumor suppressor: A master regulator of diverse cellular processes and therapeutic target in cancer. Biochem. Biophys. Res. Commun. 2010, 396, 85–89. [Google Scholar] [CrossRef] [PubMed]
  87. Gartel, A.L.; Tyner, A.L. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol. Cancer Ther. 2002, 1, 639–649. [Google Scholar] [PubMed]
  88. Kim, Y.A.; Rhee, S.H.; Park, K.Y.; Choi, Y.H. Antiproliferative effect of resveratrol in human prostate carcinoma cells. J. Med. Food 2003, 6, 273–280. [Google Scholar] [CrossRef] [PubMed]
  89. Kim, Y.A.; Lee, W.H.; Choi, T.H.; Rhee, S.H.; Park, K.Y.; Choi, Y.H. Involvement of p21WAF1/CIP1, pRB, Bax and NF-κB in induction of growth arrest and apoptosis by resveratrol in human lung carcinoma A549 cells. Int. J. Oncol. 2003, 23, 1143–1149. [Google Scholar] [CrossRef] [PubMed]
  90. Ahmad, N.; Adhami, V.M.; Afaq, F.; Feyes, D.K.; Mukhtar, H. Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin. Cancer Res. 2001, 7, 1466–1473. [Google Scholar] [PubMed]
  91. Dorrie, J.; Gerauer, H.; Wachter, Y.; Zunino, S.J. Resveratrol induces extensive apoptosis by depolarizing mitochondrial membranes and activating caspase-9 in acute lymphoblastic leukemia cells. Cancer Res. 2001, 61, 4731–4739. [Google Scholar] [PubMed]
  92. Tinhofer, I.; Bernhard, D.; Senfter, M.; Anether, G.; Loeffler, M.; Kroemer, G.; Kofler, R.; Csordas, A.; Greil, R. Resveratrol, a tumor-suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl-2. FASEB J. 2001, 15, 1613–1615. [Google Scholar] [CrossRef] [PubMed]
  93. Naik, P.; Karrim, J.; Hanahan, D. The rise and fall of apoptosis during multistage tumorigenesis: Down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev. 1996, 10, 2105–2116. [Google Scholar] [CrossRef] [PubMed]
  94. Deigner, H.P.; Kinscherf, R. Modulating apoptosis: Current applications and prospects for future drug development. Curr. Med. Chem. 1999, 6, 399–414. [Google Scholar] [PubMed]
  95. Hengartner, M.O. The biochemistry of apoptosis. Nature 2000, 407, 770–776. [Google Scholar] [CrossRef] [PubMed]
  96. Okada, H.; Mak, T.W. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat. Rev. Cancer 2004, 4, 592–603. [Google Scholar] [CrossRef] [PubMed]
  97. Hu, W.; Kavanagh, J.J. Anticancer therapy targeting the apoptotic pathway. Lancet. Oncol. 2003, 4, 721–729. [Google Scholar] [CrossRef]
  98. Ashkenazi, A.; Dixit, V.M. Apoptosis control by death and decoy receptors. Curr. Opin. Cell Boil. 1999, 11, 255–260. [Google Scholar] [CrossRef]
  99. Nicholson, D.W.; Thornberry, N.A. Caspases: Killer proteases. Trends Biochem. Sci. 1997, 22, 299–306. [Google Scholar] [CrossRef]
  100. Van Loo, G.; Saelens, X.; van Gurp, M.; MacFarlane, M.; Martin, S.J.; Vandenabeele, P. The role of mitochondrial factors in apoptosis: A Russian roulette with more than one bullet. Cell Death Differ. 2002, 9, 1031–1042. [Google Scholar] [CrossRef] [PubMed]
  101. Du, C.; Fang, M.; Li, Y.; Li, L.; Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000, 102, 33–42. [Google Scholar] [CrossRef]
  102. Sun, X.M.; MacFarlane, M.; Zhuang, J.; Wolf, B.B.; Green, D.R.; Cohen, G.M. Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J. Boil. Chem. 1999, 274, 5053–5060. [Google Scholar] [CrossRef]
  103. Korsmeyer, S.J.; Wei, M.C.; Saito, M.; Weiler, S.; Oh, K.J.; Schlesinger, P.H. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 2000, 7, 1166–1173. [Google Scholar] [CrossRef] [PubMed]
  104. Fulda, S.; Debatin, K.M. Exploiting death receptor signaling pathways for tumor therapy. Biochim. Biophys. Acta 2004, 1705, 27–41. [Google Scholar] [CrossRef] [PubMed]
  105. Cummings, J.; Ward, T.H.; Ranson, M.; Dive, C. Apoptosis pathway-targeted drugs—From the bench to the clinic. Biochim. Biophys. Acta 2004, 1705, 53–66. [Google Scholar] [CrossRef] [PubMed]
  106. Neergheen, V.S.; Bahorun, T.; Taylor, E.W.; Jen, L.S.; Aruoma, O.I. Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention. Toxicology 2010, 278, 229–241. [Google Scholar] [CrossRef] [PubMed]
  107. Ahn, K.S.; Sethi, G.; Aggarwal, B.B. Nuclear factor-κB: From clone to clinic. Curr. Mol. Med. 2007, 7, 619–637. [Google Scholar] [CrossRef] [PubMed]
  108. Li, F.; Zhang, J.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Kumar, A.P.; Ahn, K.S.; Sethi, G. NF-κB in cancer therapy. Arch. Toxicol. 2015, 89, 711–731. [Google Scholar] [CrossRef] [PubMed]
  109. Chai, E.Z.; Shanmugam, M.K.; Arfuso, F.; Dharmarajan, A.; Wang, C.; Kumar, A.P.; Samy, R.P.; Lim, L.H.; Wang, L.; Goh, B.C.; et al. Targeting transcription factor STAT3 for cancer prevention and therapy. Pharmacol. Ther. 2016, 162, 86–97. [Google Scholar] [CrossRef] [PubMed]
  110. Sethi, G.; Sung, B.; Aggarwal, B.B. Nuclear factor-κB activation: From bench to bedside. Exp. Biol. Med. 2008, 233, 21–31. [Google Scholar] [CrossRef] [PubMed]
  111. Singh, S.S.; Yap, W.N.; Arfuso, F.; Kar, S.; Wang, C.; Cai, W.; Dharmarajan, A.M.; Sethi, G.; Kumar, A.P. Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine? World J. Gastroenterol. 2015, 21, 12261–12273. [Google Scholar] [CrossRef] [PubMed]
  112. Siveen, K.S.; Sikka, S.; Surana, R.; Dai, X.; Zhang, J.; Kumar, A.P.; Tan, B.K.; Sethi, G.; Bishayee, A. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim. Biophys. Acta 2014, 1845, 136–154. [Google Scholar] [CrossRef] [PubMed]
  113. Clement, M.V.; Hirpara, J.L.; Chawdhury, S.H.; Pervaiz, S. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 1998, 92, 996–1002. [Google Scholar] [PubMed]
  114. Delmas, D.; Rebe, C.; Lacour, S.; Filomenko, R.; Athias, A.; Gambert, P.; Cherkaoui-Malki, M.; Jannin, B.; Dubrez-Daloz, L.; Latruffe, N.; et al. Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J. Boil. Chem. 2003, 278, 41482–41490. [Google Scholar] [CrossRef] [PubMed]
  115. Micheau, O.; Solary, E.; Hammann, A.; Dimanche-Boitrel, M.T. Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J. Boil. Chem. 1999, 274, 7987–7992. [Google Scholar] [CrossRef]
  116. Petak, I.; Tillman, D.M.; Harwood, F.G.; Mihalik, R.; Houghton, J.A. Fas-dependent and -independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res. 2000, 60, 2643–2650. [Google Scholar] [PubMed]
  117. Tsan, M.F.; White, J.E.; Maheshwari, J.G.; Bremner, T.A.; Sacco, J. Resveratrol induces Fas signalling-independent apoptosis in THP-1 human monocytic leukaemia cells. Br. J. Haematol. 2000, 109, 405–412. [Google Scholar] [CrossRef] [PubMed]
  118. Bernhard, D.; Tinhofer, I.; Tonko, M.; Hubl, H.; Ausserlechner, M.J.; Greil, R.; Kofler, R.; Csordas, A. Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells. Cell Death Differ. 2000, 7, 834–842. [Google Scholar] [CrossRef] [PubMed]
  119. Delmas, D.; Solary, E.; Latruffe, N. Resveratrol, a phytochemical inducer of multiple cell death pathways: Apoptosis, autophagy and mitotic catastrophe. Curr. Med. Chem. 2011, 18, 1100–1121. [Google Scholar] [CrossRef] [PubMed]
  120. Aziz, M.H.; Nihal, M.; Fu, V.X.; Jarrard, D.F.; Ahmad, N. Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3′-kinase/Akt pathway and Bcl-2 family proteins. Mol. Cancer Ther. 2006, 5, 1335–1341. [Google Scholar] [CrossRef] [PubMed]
  121. Bhardwaj, A.; Sethi, G.; Vadhan-Raj, S.; Bueso-Ramos, C.; Takada, Y.; Gaur, U.; Nair, A.S.; Shishodia, S.; Aggarwal, B.B. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-κB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 2007, 109, 2293–2302. [Google Scholar] [CrossRef] [PubMed]
  122. Casanova, F.; Quarti, J.; da Costa, D.C.; Ramos, C.A.; da Silva, J.L.; Fialho, E. Resveratrol chemosensitizes breast cancer cells to melphalan by cell cycle arrest. J. Cell. Biochem. 2012, 113, 2586–2596. [Google Scholar] [CrossRef] [PubMed]
  123. Gokbulut, A.A.; Apohan, E.; Baran, Y. Resveratrol and quercetin-induced apoptosis of human 232B4 chronic lymphocytic leukemia cells by activation of caspase-3 and cell cycle arrest. Hematology 2013, 18, 144–150. [Google Scholar] [CrossRef] [PubMed]
  124. Frazzi, R.; Valli, R.; Tamagnini, I.; Casali, B.; Latruffe, N.; Merli, F. Resveratrol-mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation. Int. J. Cancer 2013, 132, 1013–1021. [Google Scholar] [CrossRef] [PubMed]
  125. Shankar, S.; Chen, Q.; Siddiqui, I.; Sarva, K.; Srivastava, R.K. Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4′, 5 tri-hydroxystilbene): Molecular mechanisms and therapeutic potential. J. Mol. Signal. 2007, 2, 7. [Google Scholar] [CrossRef] [PubMed]
  126. Van Ginkel, P.R.; Yan, M.B.; Bhattacharya, S.; Polans, A.S.; Kenealey, J.D. Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells. Toxicol. Appl. Pharmacol. 2015, 288, 453–462. [Google Scholar] [CrossRef] [PubMed]
  127. Faber, A.C.; Dufort, F.J.; Blair, D.; Wagner, D.; Roberts, M.F.; Chiles, T.C. Inhibition of phosphatidylinositol 3-kinase-mediated glucose metabolism coincides with resveratrol-induced cell cycle arrest in human diffuse large B-cell lymphomas. Biochem. Pharmacol. 2006, 72, 1246–1256. [Google Scholar] [CrossRef] [PubMed]
  128. Wang, Y.; Romigh, T.; He, X.; Orloff, M.S.; Silverman, R.H.; Heston, W.D.; Eng, C. Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and -independent mechanisms in prostate cancer cell lines. Hum. Mol. Genet. 2010, 19, 4319–4329. [Google Scholar] [CrossRef] [PubMed]
  129. Banerjee Mustafi, S.; Chakraborty, P.K.; Raha, S. Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70. PLoS ONE 2010, 5, e8719. [Google Scholar] [CrossRef] [PubMed]
  130. Parekh, P.; Motiwale, L.; Naik, N.; Rao, K.V. Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells. Exp. Toxicol. Pathol. 2011, 63, 167–173. [Google Scholar] [CrossRef] [PubMed]
  131. He, X.; Wang, Y.; Zhu, J.; Orloff, M.; Eng, C. Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling. Cancer Lett. 2011, 301, 168–176. [Google Scholar] [CrossRef] [PubMed]
  132. Colin, D.; Limagne, E.; Jeanningros, S.; Jacquel, A.; Lizard, G.; Athias, A.; Gambert, P.; Hichami, A.; Latruffe, N.; Solary, E.; et al. Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells. Cancer Prev. Res. 2011, 4, 1095–1106. [Google Scholar] [CrossRef] [PubMed]
  133. Pozo-Guisado, E.; Merino, J.M.; Mulero-Navarro, S.; Lorenzo-Benayas, M.J.; Centeno, F.; Alvarez-Barrientos, A.; Fernandez-Salguero, P.M. Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-κB. Int. J. Cancer 2005, 115, 74–84. [Google Scholar] [CrossRef] [PubMed]
  134. Benitez, D.A.; Hermoso, M.A.; Pozo-Guisado, E.; Fernandez-Salguero, P.M.; Castellon, E.A. Regulation of cell survival by resveratrol involves inhibition of NF κB-regulated gene expression in prostate cancer cells. Prostate 2009, 69, 1045–1054. [Google Scholar] [CrossRef] [PubMed]
  135. Cecchinato, V.; Chiaramonte, R.; Nizzardo, M.; Cristofaro, B.; Basile, A.; Sherbet, G.V.; Comi, P. Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochem. Pharmacol. 2007, 74, 1568–1574. [Google Scholar] [CrossRef] [PubMed]
  136. Kueck, A.; Opipari, A.W., Jr.; Griffith, K.A.; Tan, L.; Choi, M.; Huang, J.; Wahl, H.; Liu, J.R. Resveratrol inhibits glucose metabolism in human ovarian cancer cells. Gynecol. Oncol. 2007, 107, 450–457. [Google Scholar] [CrossRef] [PubMed]
  137. Li, Y.; Liu, J.; Liu, X.; Xing, K.; Wang, Y.; Li, F.; Yao, L. Resveratrol-induced cell inhibition of growth and apoptosis in MCF7 human breast cancer cells are associated with modulation of phosphorylated Akt and caspase-9. Appl. Biochem. Biotechnol. 2006, 135, 181–192. [Google Scholar] [CrossRef]
  138. Sexton, E.; Van Themsche, C.; LeBlanc, K.; Parent, S.; Lemoine, P.; Asselin, E. Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol. Cancer 2006, 5, 45. [Google Scholar] [CrossRef] [PubMed]
  139. Chen, Q.; Ganapathy, S.; Singh, K.P.; Shankar, S.; Srivastava, R.K. Resveratrol induces growth arrest and apoptosis through activation of FOXO transcription factors in prostate cancer cells. PLoS ONE 2010, 5, e15288. [Google Scholar] [CrossRef] [PubMed]
  140. Su, J.L.; Yang, C.Y.; Zhao, M.; Kuo, M.L.; Yen, M.L. Forkhead proteins are critical for bone morphogenetic protein-2 regulation and anti-tumor activity of resveratrol. J. Boil. Chem. 2007, 282, 19385–19398. [Google Scholar] [CrossRef] [PubMed]
  141. Yu, R.; Hebbar, V.; Kim, D.W.; Mandlekar, S.; Pezzuto, J.M.; Kong, A.N. Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with mitogen-activated protein kinase pathways. Mol. Pharmacol. 2001, 60, 217–224. [Google Scholar] [PubMed]
  142. Miloso, M.; Bertelli, A.A.; Nicolini, G.; Tredici, G. Resveratrol-induced activation of the mitogen-activated protein kinases, ERK1 and ERK2, in human neuroblastoma SH-SY5Y cells. Neurosci. Lett. 1999, 264, 141–144. [Google Scholar] [CrossRef]
  143. Lin, H.Y.; Shih, A.; Davis, F.B.; Tang, H.Y.; Martino, L.J.; Bennett, J.A.; Davis, P.J. Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. J. Urol. 2002, 168, 748–755. [Google Scholar] [CrossRef]
  144. Zhang, S.; Cao, H.J.; Davis, F.B.; Tang, H.Y.; Davis, P.J.; Lin, H.Y. Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells. Br. J. Cancer 2004, 91, 178–185. [Google Scholar] [CrossRef] [PubMed]
  145. Bergh, J.J.; Lin, H.Y.; Lansing, L.; Mohamed, S.N.; Davis, F.B.; Mousa, S.; Davis, P.J. Integrin αVβ3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 2005, 146, 2864–2871. [Google Scholar] [CrossRef] [PubMed]
  146. Lin, H.Y.; Tang, H.Y.; Keating, T.; Wu, Y.H.; Shih, A.; Hammond, D.; Sun, M.; Hercbergs, A.; Davis, F.B.; Davis, P.J. Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: Both actions are integrin and ERK mediated. Carcinogenesis 2008, 29, 62–69. [Google Scholar] [CrossRef] [PubMed]
  147. Lin, H.Y.; Sun, M.; Tang, H.Y.; Simone, T.M.; Wu, Y.H.; Grandis, J.R.; Cao, H.J.; Davis, P.J.; Davis, F.B. Resveratrol causes COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer cells. J. Cell. Biochem. 2008, 104, 2131–2142. [Google Scholar] [CrossRef] [PubMed]
  148. Lin, C.; Crawford, D.R.; Lin, S.; Hwang, J.; Sebuyira, A.; Meng, R.; Westfall, J.E.; Tang, H.Y.; Lin, S.; Yu, P.Y.; et al. Inducible COX-2-dependent apoptosis in human ovarian cancer cells. Carcinogenesis 2011, 32, 19–26. [Google Scholar] [CrossRef] [PubMed]
  149. Lassus, P.; Roux, P.; Zugasti, O.; Philips, A.; Fort, P.; Hibner, U. Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway. Oncogene 2000, 19, 2377–2385. [Google Scholar] [CrossRef] [PubMed]
  150. Dong, Z. Molecular mechanism of the chemopreventive effect of resveratrol. Mutat. Res. 2003, 523–524, 145–150. [Google Scholar] [CrossRef]
  151. She, Q.B.; Huang, C.; Zhang, Y.; Dong, Z. Involvement of c-jun NH(2)-terminal kinases in resveratrol-induced activation of p53 and apoptosis. Mol. Carcinog. 2002, 33, 244–250. [Google Scholar] [CrossRef] [PubMed]
  152. Shimizu, T.; Nakazato, T.; Xian, M.J.; Sagawa, M.; Ikeda, Y.; Kizaki, M. Resveratrol induces apoptosis of human malignant B cells by activation of caspase-3 and p38 MAP kinase pathways. Biochem. Pharmacol. 2006, 71, 742–750. [Google Scholar] [CrossRef] [PubMed]
  153. She, Q.B.; Bode, A.M.; Ma, W.Y.; Chen, N.Y.; Dong, Z. Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res. 2001, 61, 1604–1610. [Google Scholar] [PubMed]
  154. Jazirehi, A.R.; Bonavida, B. Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin’s lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. Mol. Cancer Ther. 2004, 3, 71–84. [Google Scholar] [PubMed]
  155. Mann, A.P.; Verma, A.; Sethi, G.; Manavathi, B.; Wang, H.; Fok, J.Y.; Kunnumakkara, A.B.; Kumar, R.; Aggarwal, B.B.; Mehta, K. Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-κB in cancer cells: Delineation of a novel pathway. Cancer Res. 2006, 66, 8788–8795. [Google Scholar] [CrossRef] [PubMed]
  156. Qiao, L.; Zhang, H.; Yu, J.; Francisco, R.; Dent, P.; Ebert, M.P.; Rocken, C.; Farrell, G. Constitutive activation of NF-κB in human hepatocellular carcinoma: Evidence of a cytoprotective role. Hum. Gene Ther. 2006, 17, 280–290. [Google Scholar] [CrossRef] [PubMed]
  157. Baby, J.; Pickering, B.F.; Vashisht Gopal, Y.N.; Van Dyke, M.W. Constitutive and inducible nuclear factor-κB in immortalized normal human bronchial epithelial and non-small cell lung cancer cell lines. Cancer Lett. 2007, 255, 85–94. [Google Scholar] [CrossRef] [PubMed]
  158. Lenz, G.; Davis, R.E.; Ngo, V.N.; Lam, L.; George, T.C.; Wright, G.W.; Dave, S.S.; Zhao, H.; Xu, W.; Rosenwald, A.; et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008, 319, 1676–1679. [Google Scholar] [CrossRef] [PubMed]
  159. Sughra, K.; Birbach, A.; de Martin, R.; Schmid, J.A. Interaction of the TNFR-receptor associated factor TRAF1 with I-κB kinase-2 and TRAF2 indicates a regulatory function for NF-κB signaling. PLoS ONE 2010, 5, e12683. [Google Scholar] [CrossRef] [PubMed]
  160. Csaki, C.; Mobasheri, A.; Shakibaei, M. Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: Inhibition of IL-1β-induced NF-κB-mediated inflammation and apoptosis. Arthritis Res. Ther. 2009, 11, R165. [Google Scholar] [CrossRef] [PubMed]
  161. Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 2009, 9, 798–809. [Google Scholar] [CrossRef] [PubMed]
  162. Hoesel, B.; Schmid, J.A. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer 2013, 12, 86. [Google Scholar] [CrossRef] [PubMed]
  163. Johnston, P.A.; Grandis, J.R. STAT3 signaling: Anticancer strategies and challenges. Mol. Interv. 2011, 11, 18–26. [Google Scholar] [CrossRef] [PubMed]
  164. Yenari, M.A.; Han, H.S. Influence of hypothermia on post-ischemic inflammation: Role of nuclear factor kappa B (NFκB). Neurochem. Int. 2006, 49, 164–169. [Google Scholar] [CrossRef] [PubMed]
  165. Kim, C.; Baek, S.H.; Um, J.Y.; Shim, B.S.; Ahn, K.S. Resveratrol attenuates constitutive STAT3 and STAT5 activation through induction of PTPepsilon and SHP-2 tyrosine phosphatases and potentiates sorafenib-induced apoptosis in renal cell carcinoma. BMC Nephrol. 2016, 17, 19. [Google Scholar] [CrossRef] [PubMed]
  166. Wen, S.; Li, H.; Wu, M.L.; Fan, S.H.; Wang, Q.; Shu, X.H.; Kong, Q.Y.; Chen, X.Y.; Liu, J. Inhibition of NF-κB signaling commits resveratrol-treated medulloblastoma cells to apoptosis without neuronal differentiation. J. Neuro-Oncol. 2011, 104, 169–177. [Google Scholar] [CrossRef] [PubMed]
  167. Fan, Y.; Mao, R.; Yang, J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 2013, 4, 176–185. [Google Scholar] [CrossRef] [PubMed]
  168. Steele, V.E.; Hawk, E.T.; Viner, J.L.; Lubet, R.A. Mechanisms and applications of non-steroidal anti-inflammatory drugs in the chemoprevention of cancer. Mutat. Res. 2003, 523–524, 137–144. [Google Scholar] [CrossRef]
  169. Donnelly, L.E.; Newton, R.; Kennedy, G.E.; Fenwick, P.S.; Leung, R.H.; Ito, K.; Russell, R.E.; Barnes, P.J. Anti-inflammatory effects of resveratrol in lung epithelial cells: Molecular mechanisms. Am. J. Physiol. Lung Cell. Mol. Physiol. 2004, 287, L774–L783. [Google Scholar] [CrossRef] [PubMed]
  170. Pinto, M.C.; Garcia-Barrado, J.A.; Macias, P. Resveratrol is a potent inhibitor of the dioxygenase activity of lipoxygenase. J. Agric. Food Chem. 1999, 47, 4842–4846. [Google Scholar] [CrossRef] [PubMed]
  171. Baek, S.H.; Ko, J.H.; Lee, H.; Jung, J.; Kong, M.; Lee, J.W.; Lee, J.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; et al. Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells. Phytomedicine 2016, 23, 566–577. [Google Scholar] [CrossRef] [PubMed]
  172. Nelson, A.R.; Fingleton, B.; Rothenberg, M.L.; Matrisian, L.M. Matrix metalloproteinases: Biologic activity and clinical implications. J. Clin. Oncol. 2000, 18, 1135–1149. [Google Scholar] [CrossRef] [PubMed]
  173. Jinga, D.C.; BLiDARu, A.; Condrea, I.; Ardeleanu, C.; Dragomir, C.; Szegli, G.; Stefanescu, M.; Matache, C. MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: Correlations with prognostic factors. J. Cell. Mol. Med. 2006, 10, 499–510. [Google Scholar] [CrossRef] [PubMed]
  174. Yu, H.; Pan, C.; Zhao, S.; Wang, Z.; Zhang, H.; Wu, W. Resveratrol inhibits tumor necrosis factor-alpha-mediated matrix metalloproteinase-9 expression and invasion of human hepatocellular carcinoma cells. Biomed. Pharmacother. 2008, 62, 366–372. [Google Scholar] [CrossRef] [PubMed]
  175. Weng, C.J.; Wu, C.F.; Huang, H.W.; Wu, C.H.; Ho, C.T.; Yen, G.C. Evaluation of anti-invasion effect of resveratrol and related methoxy analogues on human hepatocarcinoma cells. J. Agric. Food Chem. 2010, 58, 2886–2894. [Google Scholar] [CrossRef] [PubMed]
  176. Lee, M.F.; Pan, M.H.; Chiou, Y.S.; Cheng, A.C.; Huang, H. Resveratrol modulates MED28 (Magicin/EG-1) expression and inhibits epidermal growth factor (EGF)-induced migration in MDA-MB-231 human breast cancer cells. J. Agric. Food Chem. 2011, 59, 11853–11861. [Google Scholar] [CrossRef] [PubMed]
  177. Castino, R.; Pucer, A.; Veneroni, R.; Morani, F.; Peracchio, C.; Lah, T.T.; Isidoro, C. Resveratrol reduces the invasive growth and promotes the acquisition of a long-lasting differentiated phenotype in human glioblastoma cells. J. Agric. Food Chem. 2011, 59, 4264–4272. [Google Scholar] [CrossRef] [PubMed]
  178. Vergara, D.; Valente, C.M.; Tinelli, A.; Siciliano, C.; Lorusso, V.; Acierno, R.; Giovinazzo, G.; Santino, A.; Storelli, C.; Maffia, M. Resveratrol inhibits the epidermal growth factor-induced epithelial mesenchymal transition in MCF-7 cells. Cancer Lett. 2011, 310, 1–8. [Google Scholar] [CrossRef] [PubMed]
  179. Cao, Z.; Fang, J.; Xia, C.; Shi, X.; Jiang, B.H. trans-3,4,5′-Trihydroxystibene inhibits hypoxia-inducible factor 1α and vascular endothelial growth factor expression in human ovarian cancer cells. Clin. Cancer Res. 2004, 10, 5253–5263. [Google Scholar] [CrossRef] [PubMed]
  180. Trapp, V.; Parmakhtiar, B.; Papazian, V.; Willmott, L.; Fruehauf, J.P. Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma-endothelial cell co-culture. Angiogenesis 2010, 13, 305–315. [Google Scholar] [CrossRef] [PubMed]
  181. Zhang, M.; Li, W.; Yu, L.; Wu, S. The suppressive effect of resveratrol on HIF-1α and VEGF expression after warm ischemia and reperfusion in rat liver. PLoS ONE 2014, 9, e109589. [Google Scholar] [CrossRef] [PubMed]
  182. Seong, H.; Ryu, J.; Jeong, J.Y.; Chung, I.Y.; Han, Y.S.; Hwang, S.H.; Park, J.M.; Kang, S.S.; Seo, S.W. Resveratrol suppresses vascular endothelial growth factor secretion via inhibition of CXC-chemokine receptor 4 expression in ARPE-19 cells. Mol. Med. Rep. 2015, 12, 1479–1484. [Google Scholar] [CrossRef] [PubMed]
  183. Thiery, J.P.; Acloque, H.; Huang, R.Y.; Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139, 871–890. [Google Scholar] [CrossRef] [PubMed]
  184. Chaffer, C.L.; Weinberg, R.A. A perspective on cancer cell metastasis. Science 2011, 331, 1559–1564. [Google Scholar] [CrossRef] [PubMed]
  185. Xu, Q.; Zong, L.; Chen, X.; Jiang, Z.; Nan, L.; Li, J.; Duan, W.; Lei, J.; Zhang, L.; Ma, J.; et al. Resveratrol in the treatment of pancreatic cancer. Ann. N. Y. Acad. Sci. 2015, 1348, 10–19. [Google Scholar] [CrossRef] [PubMed]
  186. Blobe, G.C.; Schiemann, W.P.; Lodish, H.F. Role of transforming growth factor β in human disease. N. Engl. J. Med. 2000, 342, 1350–1358. [Google Scholar] [CrossRef] [PubMed]
  187. Heldin, C.H.; Vanlandewijck, M.; Moustakas, A. Regulation of EMT by TGFβ in cancer. FEBS Lett. 2012, 586, 1959–1970. [Google Scholar] [CrossRef] [PubMed]
  188. Wang, H.; Zhang, H.; Tang, L.; Chen, H.; Wu, C.; Zhao, M.; Yang, Y.; Chen, X.; Liu, G. Resveratrol inhibits TGF-β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion and metastasis. Toxicology 2013, 303, 139–146. [Google Scholar] [CrossRef] [PubMed]
  189. Ji, Q.; Liu, X.; Han, Z.; Zhou, L.; Sui, H.; Yan, L.; Jiang, H.; Ren, J.; Cai, J.; Li, Q. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC Cancer 2015, 15, 97. [Google Scholar] [CrossRef] [PubMed]
  190. Huber, M.A.; Azoitei, N.; Baumann, B.; Grunert, S.; Sommer, A.; Pehamberger, H.; Kraut, N.; Beug, H.; Wirth, T. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Investig. 2004, 114, 569–581. [Google Scholar] [CrossRef] [PubMed]
  191. Huber, M.A.; Beug, H.; Wirth, T. Epithelial-mesenchymal transition: NF-κB takes center stage. Cell Cycle 2004, 3, 1477–1480. [Google Scholar] [CrossRef] [PubMed]
  192. Maier, H.J.; Schmidt-Strassburger, U.; Huber, M.A.; Wiedemann, E.M.; Beug, H.; Wirth, T. NF-κB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 2010, 295, 214–228. [Google Scholar] [CrossRef] [PubMed]
  193. Chua, H.L.; Bhat-Nakshatri, P.; Clare, S.E.; Morimiya, A.; Badve, S.; Nakshatri, H. NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: Potential involvement of ZEB-1 and ZEB-2. Oncogene 2007, 26, 711–724. [Google Scholar] [CrossRef] [PubMed]
  194. Min, C.; Eddy, S.F.; Sherr, D.H.; Sonenshein, G.E. NF-κB and epithelial to mesenchymal transition of cancer. J. Cell. Biochem. 2008, 104, 733–744. [Google Scholar] [CrossRef] [PubMed]
  195. Barbera, M.J.; Puig, I.; Dominguez, D.; Julien-Grille, S.; Guaita-Esteruelas, S.; Peiro, S.; Baulida, J.; Franci, C.; Dedhar, S.; Larue, L.; et al. Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 2004, 23, 7345–7354. [Google Scholar] [CrossRef] [PubMed]
  196. Bloomston, M.; Zervos, E.E.; Rosemurgy, A.S., II. Matrix metalloproteinases and their role in pancreatic cancer: A review of preclinical studies and clinical trials. Ann. Surg. Oncol. 2002, 9, 668–674. [Google Scholar] [CrossRef] [PubMed]
  197. Li, W.; Ma, J.; Ma, Q.; Li, B.; Han, L.; Liu, J.; Xu, Q.; Duan, W.; Yu, S.; Wang, F.; et al. Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway. Curr. Med. Chem. 2013, 20, 4185–4194. [Google Scholar] [CrossRef] [PubMed]
  198. Hao, Y.; Huang, W.; Liao, M.; Zhu, Y.; Liu, H.; Hao, C.; Liu, G.; Zhang, G.; Feng, H.; Ning, X.; et al. The inhibition of resveratrol to human skin squamous cell carcinoma A431 xenografts in nude mice. Fitoterapia 2013, 86, 84–91. [Google Scholar] [CrossRef] [PubMed]
  199. Kapadia, G.J.; Azuine, M.A.; Tokuda, H.; Takasaki, M.; Mukainaka, T.; Konoshima, T.; Nishino, H. Chemopreventive effect of resveratrol, sesamol, sesame oil and sunflower oil in the Epstein-Barr virus early antigen activation assay and the mouse skin two-stage carcinogenesis. Pharmacol. Res. 2002, 45, 499–505. [Google Scholar] [CrossRef] [PubMed]
  200. Soleas, G.J.; Grass, L.; Josephy, P.D.; Goldberg, D.M.; Diamandis, E.P. A comparison of the anticarcinogenic properties of four red wine polyphenols. Clin. Biochem. 2002, 35, 119–124. [Google Scholar] [CrossRef]
  201. Kalra, N.; Roy, P.; Prasad, S.; Shukla, Y. Resveratrol induces apoptosis involving mitochondrial pathways in mouse skin tumorigenesis. Life Sci. 2008, 82, 348–358. [Google Scholar] [CrossRef] [PubMed]
  202. Afaq, F.; Adhami, V.M.; Ahmad, N. Prevention of short-term ultraviolet B radiation-mediated damages by resveratrol in SKH-1 hairless mice. Toxicol. Appl. Pharmacol. 2003, 186, 28–37. [Google Scholar] [CrossRef]
  203. Reagan-Shaw, S.; Afaq, F.; Aziz, M.H.; Ahmad, N. Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin. Oncogene 2004, 23, 5151–5160. [Google Scholar] [CrossRef] [PubMed]
  204. Aziz, M.H.; Reagan-Shaw, S.; Wu, J.; Longley, B.J.; Ahmad, N. Chemoprevention of skin cancer by grape constituent resveratrol: Relevance to human disease? FASEB J. 2005, 19, 1193–1195. [Google Scholar] [CrossRef] [PubMed]
  205. Aziz, M.H.; Afaq, F.; Ahmad, N. Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in survivin. Photochem. Photobiol. 2005, 81, 25–31. [Google Scholar] [CrossRef] [PubMed]
  206. Caltagirone, S.; Rossi, C.; Poggi, A.; Ranelletti, F.O.; Natali, P.G.; Brunetti, M.; Aiello, F.B.; Piantelli, M. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int. J. Cancer 2000, 87, 595–600. [Google Scholar] [CrossRef]
  207. Provinciali, M.; Re, F.; Donnini, A.; Orlando, F.; Bartozzi, B.; Di Stasio, G.; Smorlesi, A. Effect of resveratrol on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Int. J. Cancer 2005, 115, 36–45. [Google Scholar] [CrossRef] [PubMed]
  208. Garvin, S.; Ollinger, K.; Dabrosin, C. Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett. 2006, 231, 113–122. [Google Scholar] [CrossRef] [PubMed]
  209. Mohapatra, P.; Satapathy, S.R.; Das, D.; Siddharth, S.; Choudhuri, T.; Kundu, C.N. Resveratrol mediated cell death in cigarette smoke transformed breast epithelial cells is through induction of p21Waf1/Cip1 and inhibition of long patch base excision repair pathway. Toxicol. Appl. Pharmacol. 2014, 275, 221–231. [Google Scholar] [CrossRef] [PubMed]
  210. Banerjee, S.; Bueso-Ramos, C.; Aggarwal, B.B. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: Role of nuclear factor-κB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 2002, 62, 4945–4954. [Google Scholar] [PubMed]
  211. Whitsett, T.; Carpenter, M.; Lamartiniere, C.A. Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats. J. Carcinog. 2006, 5, 15. [Google Scholar] [CrossRef] [PubMed]
  212. Bhat, K.P.; Lantvit, D.; Christov, K.; Mehta, R.G.; Moon, R.C.; Pezzuto, J.M. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res. 2001, 61, 7456–7463. [Google Scholar] [PubMed]
  213. Schlachterman, A.; Valle, F.; Wall, K.M.; Azios, N.G.; Castillo, L.; Morell, L.; Washington, A.V.; Cubano, L.A.; Dharmawardhane, S.F. Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl. Oncol. 2008, 1, 19–27. [Google Scholar] [CrossRef] [PubMed]
  214. Ganapathy, S.; Chen, Q.; Singh, K.P.; Shankar, S.; Srivastava, R.K. Resveratrol enhances antitumor activity of TRAIL in prostate cancer xenografts through activation of FOXO transcription factor. PLoS ONE 2010, 5, e15627. [Google Scholar] [CrossRef] [PubMed]
  215. Li, K.; Dias, S.J.; Rimando, A.M.; Dhar, S.; Mizuno, C.S.; Penman, A.D.; Lewin, J.R.; Levenson, A.S. Pterostilbene acts through metastasis-associated protein 1 to inhibit tumor growth, progression and metastasis in prostate cancer. PLoS ONE 2013, 8, e57542. [Google Scholar] [CrossRef] [PubMed]
  216. Harper, C.E.; Patel, B.B.; Wang, J.; Arabshahi, A.; Eltoum, I.A.; Lamartiniere, C.A. Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis 2007, 28, 1946–1953. [Google Scholar] [CrossRef] [PubMed]
  217. Seeni, A.; Takahashi, S.; Takeshita, K.; Tang, M.; Sugiura, S.; Sato, S.Y.; Shirai, T. Suppression of prostate cancer growth by resveratrol in the transgenic rat for adenocarcinoma of prostate (TRAP) model. APJCP 2008, 9, 7–14. [Google Scholar] [PubMed]
  218. Kimura, Y.; Okuda, H. Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice. J. Nutr. 2001, 131, 1844–1849. [Google Scholar] [PubMed]
  219. Yin, H.T.; Tian, Q.Z.; Guan, L.; Zhou, Y.; Huang, X.E.; Zhang, H. In vitro and in vivo evaluation of the antitumor efficiency of resveratrol against lung cancer. APJCP 2013, 14, 1703–1706. [Google Scholar] [CrossRef] [PubMed]
  220. Busquets, S.; Ametller, E.; Fuster, G.; Olivan, M.; Raab, V.; Argiles, J.M.; Lopez-Soriano, F.J. Resveratrol, a natural diphenol, reduces metastatic growth in an experimental cancer model. Cancer Lett. 2007, 245, 144–148. [Google Scholar] [CrossRef] [PubMed]
  221. Lee, E.O.; Lee, H.J.; Hwang, H.S.; Ahn, K.S.; Chae, C.; Kang, K.S.; Lu, J.; Kim, S.H. Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis 2006, 27, 2059–2069. [Google Scholar] [CrossRef] [PubMed]
  222. Sengottuvelan, M.; Nalini, N. Dietary supplementation of resveratrol suppresses colonic tumour incidence in 1,2-dimethylhydrazine-treated rats by modulating biotransforming enzymes and aberrant crypt foci development. Br. J. Nutr. 2006, 96, 145–153. [Google Scholar] [CrossRef] [PubMed]
  223. Huderson, A.C.; Myers, J.N.; Niaz, M.S.; Washington, M.K.; Ramesh, A. Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol. J. Nutr. Biochem. 2013, 24, 713–724. [Google Scholar] [CrossRef] [PubMed]
  224. Tessitore, L.; Davit, A.; Sarotto, I.; Caderni, G. Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis 2000, 21, 1619–1622. [Google Scholar] [CrossRef] [PubMed]
  225. Schneider, Y.; Duranton, B.; Gosse, F.; Schleiffer, R.; Seiler, N.; Raul, F. Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis. Nutr. Cancer 2001, 39, 102–107. [Google Scholar] [CrossRef] [PubMed]
  226. Sale, S.; Tunstall, R.G.; Ruparelia, K.C.; Potter, G.A.; Steward, W.P.; Gescher, A.J. Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) on adenoma development in the Apc(Min+) mouse and cyclooxygenase-2 in human-derived colon cancer cells. Int. J. Cancer 2005, 115, 194–201. [Google Scholar] [CrossRef] [PubMed]
  227. Miura, D.; Miura, Y.; Yagasaki, K. Hypolipidemic action of dietary resveratrol, a phytoalexin in grapes and red wine, in hepatoma-bearing rats. Life Sci. 2003, 73, 1393–1400. [Google Scholar] [CrossRef]
  228. Carbo, N.; Costelli, P.; Baccino, F.M.; Lopez-Soriano, F.J.; Argiles, J.M. Resveratrol, a natural product present in wine, decreases tumour growth in a rat tumour model. Biochem. Biophys. Res. Commun. 1999, 254, 739–743. [Google Scholar] [CrossRef] [PubMed]
  229. Liu, H.S.; Pan, C.E.; Yang, W.; Liu, X.M. Antitumor and immunomodulatory activity of resveratrol on experimentally implanted tumor of H22 in Balb/c mice. World J. Gastroenterol. 2003, 9, 1474–1476. [Google Scholar] [CrossRef] [PubMed]
  230. Yu, L.; Sun, Z.J.; Wu, S.L.; Pan, C.E. Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer. World J. Gastroenterol. 2003, 9, 2341–2343. [Google Scholar] [CrossRef] [PubMed]
  231. Wu, S.L.; Sun, Z.J.; Yu, L.; Meng, K.W.; Qin, X.L.; Pan, C.E. Effect of resveratrol and in combination with 5-FU on murine liver cancer. World J. Gastroenterol. 2004, 10, 3048–3052. [Google Scholar] [CrossRef] [PubMed]
  232. Yang, H.L.; Chen, W.Q.; Cao, X.; Worschech, A.; Du, L.F.; Fang, W.Y.; Xu, Y.Y.; Stroncek, D.F.; Li, X.; Wang, E.; et al. Caveolin-1 enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model. J. Transl. Med. 2009, 7, 22. [Google Scholar] [CrossRef] [PubMed]
  233. Kweon, S.; Kim, Y.; Choi, H. Grape extracts suppress the formation of preneoplastic foci and activity of fatty acid synthase in rat liver. Exp. Mol. Med. 2003, 35, 371–378. [Google Scholar] [CrossRef] [PubMed]
  234. Bishayee, A.; Dhir, N. Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: Inhibition of cell proliferation and induction of apoptosis. Chem.-Biol. Interact. 2009, 179, 131–144. [Google Scholar] [CrossRef] [PubMed]
  235. Boily, G.; He, X.H.; Pearce, B.; Jardine, K.; McBurney, M.W. SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 2009, 28, 2882–2893. [Google Scholar] [CrossRef] [PubMed]
  236. Kowalczyk, M.C.; Junco, J.J.; Kowalczyk, P.; Tolstykh, O.; Hanausek, M.; Slaga, T.J.; Walaszek, Z. Effects of combined phytochemicals on skin tumorigenesis in SENCAR mice. Int. J. Oncol. 2013, 43, 911–918. [Google Scholar] [CrossRef] [PubMed]
  237. Szaefer, H.; Krajka-Kuzniak, V.; Baer-Dubowska, W. The effect of initiating doses of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene on the expression of PAH activating enzymes and its modulation by plant phenols. Toxicology 2008, 251, 28–34. [Google Scholar] [CrossRef] [PubMed]
  238. Roy, P.; Kalra, N.; Prasad, S.; George, J.; Shukla, Y. Chemopreventive potential of resveratrol in mouse skin tumors through regulation of mitochondrial and PI3K/AKT signaling pathways. Pharm. Res. 2009, 26, 211–217. [Google Scholar] [CrossRef] [PubMed]
  239. Yusuf, N.; Nasti, T.H.; Meleth, S.; Elmets, C.A. Resveratrol enhances cell-mediated immune response to DMBA through TLR4 and prevents DMBA induced cutaneous carcinogenesis. Mol. Carcinog. 2009, 48, 713–723. [Google Scholar] [CrossRef] [PubMed]
  240. Jang, M.; Pezzuto, J.M. Effects of resveratrol on 12-O-tetradecanoylphorbol-13-acetate-induced oxidative events and gene expression in mouse skin. Cancer Lett. 1998, 134, 81–89. [Google Scholar] [CrossRef]
  241. Kundu, J.K.; Chun, K.S.; Kim, S.O.; Surh, Y.J. Resveratrol inhibits phorbol ester-induced cyclooxygenase-2 expression in mouse skin: MAPKs and AP-1 as potential molecular targets. BioFactors 2004, 21, 33–39. [Google Scholar] [CrossRef] [PubMed]
  242. Cichocki, M.; Paluszczak, J.; Szaefer, H.; Piechowiak, A.; Rimando, A.M.; Baer-Dubowska, W. Pterostilbene is equally potent as resveratrol in inhibiting 12-O-tetradecanoylphorbol-13-acetate activated NFκB, AP-1, COX-2, and iNOS in mouse epidermis. Mol. Nutr. Food Res. 2008, 52, S62–S70. [Google Scholar] [CrossRef] [PubMed]
  243. Kim, K.H.; Back, J.H.; Zhu, Y.; Arbesman, J.; Athar, M.; Kopelovich, L.; Kim, A.L.; Bickers, D.R. Resveratrol targets transforming growth factor-β2 signaling to block UV-induced tumor progression. J. Investig. Dermatol. 2011, 131, 195–202. [Google Scholar] [CrossRef] [PubMed]
  244. Sirerol, J.A.; Feddi, F.; Mena, S.; Rodriguez, M.L.; Sirera, P.; Aupi, M.; Perez, S.; Asensi, M.; Ortega, A.; Estrela, J.M. Topical treatment with pterostilbene, a natural phytoalexin, effectively protects hairless mice against UVB radiation-induced skin damage and carcinogenesis. Free Radic. Boil. Med. 2015, 85, 1–11. [Google Scholar] [CrossRef] [PubMed]
  245. Bhattacharya, S.; Darjatmoko, S.R.; Polans, A.S. Resveratrol modulates the malignant properties of cutaneous melanoma through changes in the activation and attenuation of the antiapoptotic protooncogenic protein Akt/PKB. Melanoma Res. 2011, 21, 180–187. [Google Scholar] [CrossRef] [PubMed]
  246. Asensi, M.; Medina, I.; Ortega, A.; Carretero, J.; Bano, M.C.; Obrador, E.; Estrela, J.M. Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic. Boil. Med. 2002, 33, 387–398. [Google Scholar] [CrossRef]
  247. Niles, R.M.; Cook, C.P.; Meadows, G.G.; Fu, Y.M.; McLaughlin, J.L.; Rankin, G.O. Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth. J. Nutr. 2006, 136, 2542–2546. [Google Scholar] [PubMed]
  248. Qin, W.; Zhang, K.; Clarke, K.; Weiland, T.; Sauter, E.R. Methylation and miRNA effects of resveratrol on mammary tumors vs. normal tissue. Nutr. Cancer 2014, 66, 270–277. [Google Scholar] [CrossRef] [PubMed]
  249. Zander, S.A.; Kersbergen, A.; Sol, W.; Gonggrijp, M.; van de Wetering, K.; Jonkers, J.; Borst, P.; Rottenberg, S. Lack of ABCG2 shortens latency of BRCA1-deficient mammary tumors and this is not affected by genistein or resveratrol. Cancer Prev. Res. 2012, 5, 1053–1060. [Google Scholar] [CrossRef] [PubMed]
  250. Sato, M.; Pei, R.J.; Yuri, T.; Danbara, N.; Nakane, Y.; Tsubura, A. Prepubertal resveratrol exposure accelerates N-methyl-N-nitrosourea-induced mammary carcinoma in female Sprague-Dawley rats. Cancer Lett. 2003, 202, 137–145. [Google Scholar] [CrossRef] [PubMed]
  251. Bove, K.; Lincoln, D.W.; Tsan, M.F. Effect of resveratrol on growth of 4T1 breast cancer cells in vitro and in vivo. Biochem. Biophys. Res. Commun. 2002, 291, 1001–1005. [Google Scholar] [CrossRef] [PubMed]
  252. Lee, H.S.; Ha, A.W.; Kim, W.K. Effect of resveratrol on the metastasis of 4T1 mouse breast cancer cells in vitro and in vivo. Nutr. Res. Pract. 2012, 6, 294–300. [Google Scholar] [CrossRef] [PubMed]
  253. Fu, Y.; Chang, H.; Peng, X.; Bai, Q.; Yi, L.; Zhou, Y.; Zhu, J.; Mi, M. Resveratrol inhibits breast cancer stem-like cells and induces autophagy via suppressing Wnt/β-catenin signaling pathway. PLoS ONE 2014, 9, e102535. [Google Scholar] [CrossRef] [PubMed]
  254. Wang, T.T.; Hudson, T.S.; Wang, T.C.; Remsberg, C.M.; Davies, N.M.; Takahashi, Y.; Kim, Y.S.; Seifried, H.; Vinyard, B.T.; Perkins, S.N.; et al. Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis 2008, 29, 2001–2010. [Google Scholar] [CrossRef] [PubMed]
  255. Brizuela, L.; Dayon, A.; Doumerc, N.; Ader, I.; Golzio, M.; Izard, J.C.; Hara, Y.; Malavaud, B.; Cuvillier, O. The sphingosine kinase-1 survival pathway is a molecular target for the tumor-suppressive tea and wine polyphenols in prostate cancer. FASEB J. 2010, 24, 3882–3894. [Google Scholar] [CrossRef] [PubMed]
  256. Willett, W.C. Diet, nutrition, and avoidable cancer. Environ. Health Perspect. 1995, 103, 165–170. [Google Scholar] [CrossRef] [PubMed]
  257. Ruggeri, B.A.; Camp, F.; Miknyoczki, S. Animal models of disease: Pre-clinical animal models of cancer and their applications and utility in drug discovery. Biochem. Pharmacol. 2014, 87, 150–161. [Google Scholar] [CrossRef] [PubMed]
  258. Washington, M.K.; Powell, A.E.; Sullivan, R.; Sundberg, J.P.; Wright, N.; Coffey, R.J.; Dove, W.F. Pathology of rodent models of intestinal cancer: Progress report and recommendations. Gastroenterology 2013, 144, 705–717. [Google Scholar] [CrossRef] [PubMed]
  259. Cui, X.; Jin, Y.; Hofseth, A.B.; Pena, E.; Habiger, J.; Chumanevich, A.; Poudyal, D.; Nagarkatti, M.; Nagarkatti, P.S.; Singh, U.P.; et al. Resveratrol suppresses colitis and colon cancer associated with colitis. Cancer Prev. Res. 2010, 3, 549–559. [Google Scholar] [CrossRef] [PubMed]
  260. Liao, W.; Wei, H.; Wang, X.; Qiu, Y.; Gou, X.; Zhang, X.; Zhou, M.; Wu, J.; Wu, T.; Kou, F.; et al. Metabonomic variations associated with AOM-induced precancerous colorectal lesions and resveratrol treatment. J. Proteome Res. 2012, 11, 3436–3448. [Google Scholar] [CrossRef] [PubMed]
  261. Chiou, Y.S.; Tsai, M.L.; Nagabhushanam, K.; Wang, Y.J.; Wu, C.H.; Ho, C.T.; Pan, M.H. Pterostilbene is more potent than resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (Nrf2)-mediated antioxidant signaling pathway. J. Agric. Food Chem. 2011, 59, 2725–2733. [Google Scholar] [CrossRef] [PubMed]
  262. Sengottuvelan, M.; Senthilkumar, R.; Nalini, N. Modulatory influence of dietary resveratrol during different phases of 1,2-dimethylhydrazine induced mucosal lipid-peroxidation, antioxidant status and aberrant crypt foci development in rat colon carcinogenesis. Biochim. Biophys. Acta 2006, 1760, 1175–1183. [Google Scholar] [CrossRef] [PubMed]
  263. Alfaras, I.; Juan, M.E.; Planas, J.M. trans-Resveratrol reduces precancerous colonic lesions in dimethylhydrazine-treated rats. J. Agric. Food Chem. 2010, 58, 8104–8110. [Google Scholar] [CrossRef] [PubMed]
  264. Sengottuvelan, M.; Deeptha, K.; Nalini, N. Resveratrol ameliorates DNA damage, prooxidant and antioxidant imbalance in 1,2-dimethylhydrazine induced rat colon carcinogenesis. Chem.-Biol. Interact. 2009, 181, 193–201. [Google Scholar] [CrossRef] [PubMed]
  265. Sengottuvelan, M.; Viswanathan, P.; Nalini, N. Chemopreventive effect of trans-resveratrol—A phytoalexin against colonic aberrant crypt foci and cell proliferation in 1,2-dimethylhydrazine induced colon carcinogenesis. Carcinogenesis 2006, 27, 1038–1046. [Google Scholar] [CrossRef] [PubMed]
  266. Sengottuvelan, M.; Deeptha, K.; Nalini, N. Influence of dietary resveratrol on early and late molecular markers of 1,2-dimethylhydrazine-induced colon carcinogenesis. Nutrition 2009, 25, 1169–1176. [Google Scholar] [CrossRef] [PubMed]
  267. Saud, S.M.; Li, W.; Morris, N.L.; Matter, M.S.; Colburn, N.H.; Kim, Y.S.; Young, M.R. Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression. Carcinogenesis 2014, 35, 2778–2786. [Google Scholar] [CrossRef] [PubMed]
  268. Schneider, Y.; Vincent, F.; Duranton, B.; Badolo, L.; Gosse, F.; Bergmann, C.; Seiler, N.; Raul, F. Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. Cancer Lett. 2000, 158, 85–91. [Google Scholar] [CrossRef]
  269. Rajasekaran, D.; Elavarasan, J.; Sivalingam, M.; Ganapathy, E.; Kumar, A.; Kalpana, K.; Sakthisekaran, D. Resveratrol interferes with N-nitrosodiethylamine-induced hepatocellular carcinoma at early and advanced stages in male Wistar rats. Mol. Med. Rep. 2011, 4, 1211–1217. [Google Scholar] [PubMed]
  270. Luther, D.J.; Ohanyan, V.; Shamhart, P.E.; Hodnichak, C.M.; Sisakian, H.; Booth, T.D.; Meszaros, J.G.; Bishayee, A. Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma. Investig. New Drugs 2011, 29, 380–391. [Google Scholar] [CrossRef] [PubMed]
  271. Wu, X.; Li, C.; Xing, G.; Qi, X.; Ren, J. Resveratrol Downregulates Cyp2e1 and Attenuates Chemically Induced Hepatocarcinogenesis in SD Rats. J. Toxicol. Pathol. 2013, 26, 385–392. [Google Scholar] [CrossRef] [PubMed]
  272. Lin, H.C.; Chen, Y.F.; Hsu, W.H.; Yang, C.W.; Kao, C.H.; Tsai, T.F. Resveratrol helps recovery from fatty liver and protects against hepatocellular carcinoma induced by hepatitis B virus X protein in a mouse model. Cancer Prev. Res. 2012, 5, 952–962. [Google Scholar] [CrossRef] [PubMed]
  273. Bishayee, A.; Barnes, K.F.; Bhatia, D.; Darvesh, A.S.; Carroll, R.T. Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis. Cancer Prev. Res. 2010, 3, 753–763. [Google Scholar] [CrossRef] [PubMed]
  274. Kitamura, Y.; Umemura, T.; Kanki, K.; Kodama, Y.; Kitamoto, S.; Saito, K.; Itoh, K.; Yamamoto, M.; Masegi, T.; Nishikawa, A.; et al. Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4,5-f]quinoline. Cancer Sci. 2007, 98, 19–24. [Google Scholar] [CrossRef] [PubMed]
  275. Bishayee, A.; Waghray, A.; Barnes, K.F.; Mbimba, T.; Bhatia, D.; Chatterjee, M.; Darvesh, A.S. Suppression of the inflammatory cascade is implicated in resveratrol chemoprevention of experimental hepatocarcinogenesis. Pharm. Res. 2010, 27, 1080–1091. [Google Scholar] [CrossRef] [PubMed]
  276. Mbimba, T.; Awale, P.; Bhatia, D.; Geldenhuys, W.J.; Darvesh, A.S.; Carroll, R.T.; Bishayee, A. Alteration of hepatic proinflammatory cytokines is involved in the resveratrol-mediated chemoprevention of chemically-induced hepatocarcinogenesis. Curr. Pharm. Biotechnol. 2012, 13, 229–234. [Google Scholar] [CrossRef] [PubMed]
  277. Bishayee, A.; Petit, D.M.; Samtani, K. Angioprevention is Implicated in Resveratrol Chemoprevention of Experimental Hepatocarcinogenesis. J. Carcinog. Mutagen. 2010, 1, 102. [Google Scholar] [CrossRef]
  278. Yu, H.B.; Zhang, H.F.; Zhang, X.; Li, D.Y.; Xue, H.Z.; Pan, C.E.; Zhao, S.H. Resveratrol inhibits VEGF expression of human hepatocellular carcinoma cells through a NF-κB-mediated mechanism. Hepato-Gastroenterology 2010, 57, 1241–1246. [Google Scholar] [PubMed]
  279. Salado, C.; Olaso, E.; Gallot, N.; Valcarcel, M.; Egilegor, E.; Mendoza, L.; Vidal-Vanaclocha, F. Resveratrol prevents inflammation-dependent hepatic melanoma metastasis by inhibiting the secretion and effects of interleukin-18. J. Transl. Med. 2011, 9, 59. [Google Scholar] [CrossRef] [PubMed]
  280. Byrum, R.S.; Goulet, J.L.; Snouwaert, J.N.; Griffiths, R.J.; Koller, B.H. Determination of the contribution of cysteinyl leukotrienes and leukotriene B4 in acute inflammatory responses using 5-lipoxygenase- and leukotriene A4 hydrolase-deficient mice. J. Immunol. 1999, 163, 6810–6819. [Google Scholar] [PubMed]
  281. Bortuzzo, C.; Hanif, R.; Kashfi, K.; Staiano-Coico, L.; Shiff, S.J.; Rigas, B. The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. Biochim. Biophys. Acta 1996, 1300, 240–246. [Google Scholar] [CrossRef]
  282. Tong, W.G.; Ding, X.Z.; Hennig, R.; Witt, R.C.; Standop, J.; Pour, P.M.; Adrian, T.E. Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin. Cancer Res. 2002, 8, 3232–3242. [Google Scholar] [PubMed]
  283. Roy, S.K.; Chen, Q.; Fu, J.; Shankar, S.; Srivastava, R.K. Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors. PLoS ONE 2011, 6, e25166. [Google Scholar] [CrossRef] [PubMed]
  284. Shankar, S.; Nall, D.; Tang, S.N.; Meeker, D.; Passarini, J.; Sharma, J.; Srivastava, R.K. Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS ONE 2011, 6, e16530. [Google Scholar] [CrossRef] [PubMed]
  285. Kuroiwa, Y.; Nishikawa, A.; Kitamura, Y.; Kanki, K.; Ishii, Y.; Umemura, T.; Hirose, M. Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic carcinogenesis in hamsters. Cancer Lett. 2006, 241, 275–280. [Google Scholar] [CrossRef] [PubMed]
  286. Revel, A.; Raanani, H.; Younglai, E.; Xu, J.; Rogers, I.; Han, R.; Savouret, J.F.; Casper, R.F. Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene. JAT 2003, 23, 255–261. [Google Scholar] [CrossRef] [PubMed]
  287. Malhotra, A.; Nair, P.; Dhawan, D.K. Premature mitochondrial senescence and related ultrastructural changes during lung carcinogenesis modulation by curcumin and resveratrol. Ultrastruct. Pathol. 2012, 36, 179–184. [Google Scholar] [CrossRef] [PubMed]
  288. Malhotra, A.; Nair, P.; Dhawan, D.K. Study to evaluate molecular mechanics behind synergistic chemo-preventive effects of curcumin and resveratrol during lung carcinogenesis. PLoS ONE 2014, 9, e93820. [Google Scholar] [CrossRef] [PubMed]
  289. Yu, Y.H.; Chen, H.A.; Chen, P.S.; Cheng, Y.J.; Hsu, W.H.; Chang, Y.W.; Chen, Y.H.; Jan, Y.; Hsiao, M.; Chang, T.Y.; et al. MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol. Oncogene 2013, 32, 431–443. [Google Scholar] [CrossRef] [PubMed]
  290. Lee, K.A.; Lee, Y.J.; Ban, J.O.; Lee, Y.J.; Lee, S.H.; Cho, M.K.; Nam, H.S.; Hong, J.T.; Shim, J.H. The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1. Int. J. Mol. Med. 2012, 30, 21–27. [Google Scholar] [PubMed]
  291. Hecht, S.S.; Kenney, P.M.; Wang, M.; Trushin, N.; Agarwal, S.; Rao, A.V.; Upadhyaya, P. Evaluation of butylated hydroxyanisole, myo-inositol, curcumin, esculetin, resveratrol and lycopene as inhibitors of benzo[a]pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice. Cancer Lett. 1999, 137, 123–130. [Google Scholar] [CrossRef]
  292. Berge, G.; Ovrebo, S.; Eilertsen, E.; Haugen, A.; Mollerup, S. Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene. Br. J. Cancer 2004, 91, 1380–1383. [Google Scholar] [CrossRef] [PubMed]
  293. Shi, Q.; Geldenhuys, W.; Sutariya, V.; Bishayee, A.; Patel, I.; Bhatia, D. CArG-driven GADD45α activated by resveratrol inhibits lung cancer cells. Genes Cancer 2015, 6, 220–230. [Google Scholar] [PubMed]
  294. Berta, G.N.; Salamone, P.; Sprio, A.E.; Di Scipio, F.; Marinos, L.M.; Sapino, S.; Carlotti, M.E.; Cavalli, R.; Di Carlo, F. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch by topical application of resveratrol complexed with 2-hydroxypropyl-beta-cyclodextrin. Oral Oncol. 2010, 46, 42–48. [Google Scholar] [CrossRef] [PubMed]
  295. Woodall, C.E.; Li, Y.; Liu, Q.H.; Wo, J.; Martin, R.C. Chemoprevention of metaplasia initiation and carcinogenic progression to esophageal adenocarcinoma by resveratrol supplementation. Anti-Cancer Drugs 2009, 20, 437–443. [Google Scholar] [CrossRef] [PubMed]
  296. Lee, M.H.; Choi, B.Y.; Kundu, J.K.; Shin, Y.K.; Na, H.K.; Surh, Y.J. Resveratrol suppresses growth of human ovarian cancer cells in culture and in a murine xenograft model: Eukaryotic elongation factor 1A2 as a potential target. Cancer Res. 2009, 69, 7449–7458. [Google Scholar] [CrossRef] [PubMed]
  297. Zhou, H.B.; Chen, J.J.; Wang, W.X.; Cai, J.T.; Du, Q. Anticancer activity of resveratrol on implanted human primary gastric carcinoma cells in nude mice. World J. Gastroenterol. 2005, 11, 280–284. [Google Scholar] [CrossRef] [PubMed]
  298. Tyagi, A.; Gu, M.; Takahata, T.; Frederick, B.; Agarwal, C.; Siriwardana, S.; Agarwal, R.; Sclafani, R.A. Resveratrol selectively induces DNA Damage, independent of Smad4 expression, in its efficacy against human head and neck squamous cell carcinoma. Clin. Cancer Res. 2011, 17, 5402–5411. [Google Scholar] [CrossRef] [PubMed]
  299. Hu, F.W.; Tsai, L.L.; Yu, C.H.; Chen, P.N.; Chou, M.Y.; Yu, C.C. Impairment of tumor-initiating stem-like property and reversal of epithelial-mesenchymal transdifferentiation in head and neck cancer by resveratrol treatment. Mol. Nutr. Food Res. 2012, 56, 1247–1258. [Google Scholar] [CrossRef] [PubMed]
  300. Chen, Y.; Tseng, S.H.; Lai, H.S.; Chen, W.J. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery 2004, 136, 57–66. [Google Scholar] [CrossRef] [PubMed]
  301. Van Ginkel, P.R.; Sareen, D.; Subramanian, L.; Walker, Q.; Darjatmoko, S.R.; Lindstrom, M.J.; Kulkarni, A.; Albert, D.M.; Polans, A.S. Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria. Clin. Cancer Res. 2007, 13, 5162–5169. [Google Scholar] [CrossRef] [PubMed]
  302. Tseng, S.H.; Lin, S.M.; Chen, J.C.; Su, Y.H.; Huang, H.Y.; Chen, C.K.; Lin, P.Y.; Chen, Y. Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin. Cancer Res. 2004, 10, 2190–2202. [Google Scholar] [CrossRef] [PubMed]
  303. Brakenhielm, E.; Cao, R.; Cao, Y. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. FASEB J. 2001, 15, 1798–1800. [Google Scholar] [CrossRef] [PubMed]
  304. Li, Z.G.; Hong, T.; Shimada, Y.; Komoto, I.; Kawabe, A.; Ding, Y.; Kaganoi, J.; Hashimoto, Y.; Imamura, M. Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. Carcinogenesis 2002, 23, 1531–1536. [Google Scholar] [CrossRef] [PubMed]
  305. Yang, Q.; Wang, B.; Zang, W.; Wang, X.; Liu, Z.; Li, W.; Jia, J. Resveratrol inhibits the growth of gastric cancer by inducing G1 phase arrest and senescence in a Sirt1-dependent manner. PLoS ONE 2013, 8, e70627. [Google Scholar] [CrossRef] [PubMed]
  306. Stakleff, K.S.; Sloan, T.; Blanco, D.; Marcanthony, S.; Booth, T.D.; Bishayee, A. Resveratrol exerts differential effects in vitro and in vivo against ovarian cancer cells. APJCP 2012, 13, 1333–1340. [Google Scholar] [CrossRef] [PubMed]
  307. Patel, K.R.; Scott, E.; Brown, V.A.; Gescher, A.J.; Steward, W.P.; Brown, K. Clinical trials of resveratrol. Ann. N. Y. Acad. Sci. 2011, 1215, 161–169. [Google Scholar] [CrossRef] [PubMed]
  308. Cottart, C.H.; Nivet-Antoine, V.; Laguillier-Morizot, C.; Beaudeux, J.L. Resveratrol bioavailability and toxicity in humans. Mol. Nutr. Food Res. 2010, 54, 7–16. [Google Scholar] [CrossRef] [PubMed]
  309. Gescher, A.; Steward, W.P.; Brown, K. Resveratrol in the management of human cancer: How strong is the clinical evidence? Ann. N. Y. Acad. Sci. 2013, 1290, 12–20. [Google Scholar] [CrossRef] [PubMed]
  310. Chow, H.H.; Garland, L.L.; Hsu, C.H.; Vining, D.R.; Chew, W.M.; Miller, J.A.; Perloff, M.; Crowell, J.A.; Alberts, D.S. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev. Res. 2010, 3, 1168–1175. [Google Scholar] [CrossRef] [PubMed]
  311. Smoliga, J.M.; Blanchard, O. Enhancing the delivery of resveratrol in humans: If low bioavailability is the problem, what is the solution? Molecules 2014, 19, 17154–17172. [Google Scholar] [CrossRef] [PubMed]
  312. La Porte, C.; Voduc, N.; Zhang, G.; Seguin, I.; Tardiff, D.; Singhal, N.; Cameron, D.W. Steady-State pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin. Pharmacokinet. 2010, 49, 449–454. [Google Scholar] [CrossRef] [PubMed]
  313. Johnson, J.J.; Nihal, M.; Siddiqui, I.A.; Scarlett, C.O.; Bailey, H.H.; Mukhtar, H.; Ahmad, N. Enhancing the bioavailability of resveratrol by combining it with piperine. Mol. Nutr. Food Res. 2011, 55, 1169–1176. [Google Scholar] [CrossRef] [PubMed]
  314. Liang, L.; Liu, X.; Wang, Q.; Cheng, S.; Zhang, S.; Zhang, M. Pharmacokinetics, tissue distribution and excretion study of resveratrol and its prodrug 3,5,4′-tri-O-acetylresveratrol in rats. Phytomedicine 2013, 20, 558–563. [Google Scholar] [CrossRef] [PubMed]
  315. Howells, L.M.; Berry, D.P.; Elliott, P.J.; Jacobson, E.W.; Hoffmann, E.; Hegarty, B.; Brown, K.; Steward, W.P.; Gescher, A.J. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—Safety, pharmacokinetics, and pharmacodynamics. Cancer Prev. Res. 2011, 4, 1419–1425. [Google Scholar] [CrossRef] [PubMed]
  316. Popat, R.; Plesner, T.; Davies, F.; Cook, G.; Cook, M.; Elliott, P.; Jacobson, E.; Gumbleton, T.; Oakervee, H.; Cavenagh, J. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br. J. Haematol. 2013, 160, 714–717. [Google Scholar] [CrossRef] [PubMed]
  317. Ansari, K.A.; Vavia, P.R.; Trotta, F.; Cavalli, R. Cyclodextrin-based nanosponges for delivery of resveratrol: In vitro characterisation, stability, cytotoxicity and permeation study. AAPS PharmSciTech 2011, 12, 279–286. [Google Scholar] [CrossRef] [PubMed]
  318. Pangeni, R.; Sahni, J.K.; Ali, J.; Sharma, S.; Baboota, S. Resveratrol: Review on therapeutic potential and recent advances in drug delivery. Exp. Opin. Drug Deliv. 2014, 11, 1285–1298. [Google Scholar] [CrossRef] [PubMed]
  319. Wang, S.; Su, R.; Nie, S.; Sun, M.; Zhang, J.; Wu, D.; Moustaid-Moussa, N. Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals. J. Nutr. Biochem. 2014, 25, 363–376. [Google Scholar] [CrossRef] [PubMed]
  320. Nguyen, A.V.; Martinez, M.; Stamos, M.J.; Moyer, M.P.; Planutis, K.; Hope, C.; Holcombe, R.F. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Managen. Res. 2009, 1, 25–37. [Google Scholar]
  321. Robbins, D.H.; Itzkowitz, S.H. The molecular and genetic basis of colon cancer. Med. Clin. N. Am. 2002, 86, 1467–1495. [Google Scholar] [CrossRef]
  322. Patel, K.R.; Brown, V.A.; Jones, D.J.; Britton, R.G.; Hemingway, D.; Miller, A.S.; West, K.P.; Booth, T.D.; Perloff, M.; Crowell, J.A.; et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010, 70, 7392–7399. [Google Scholar] [CrossRef] [PubMed]
  323. Paller, C.J.; Rudek, M.A.; Zhou, X.C.; Wagner, W.D.; Hudson, T.S.; Anders, N.; Hammers, H.J.; Dowling, D.; King, S.; Antonarakis, E.S.; et al. A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination. Prostate 2015, 75, 1518–1525. [Google Scholar] [CrossRef] [PubMed]
  324. Kjaer, T.N.; Ornstrup, M.J.; Poulsen, M.M.; Jorgensen, J.O.; Hougaard, D.M.; Cohen, A.S.; Neghabat, S.; Richelsen, B.; Pedersen, S.B. Resveratrol reduces the levels of circulating androgen precursors but has no effect on, testosterone, dihydrotestosterone, PSA levels or prostate volume. A 4-month randomised trial in middle-aged men. Prostate 2015, 75, 1255–1263. [Google Scholar] [CrossRef] [PubMed]
  325. Geiszt, M.; Lekstrom, K.; Brenner, S.; Hewitt, S.M.; Dana, R.; Malech, H.L.; Leto, T.L. NAD(P)H oxidase 1, a product of differentiated colon epithelial cells, can partially replace glycoprotein 91phox in the regulated production of superoxide by phagocytes. J. Immunol. 2003, 171, 299–306. [Google Scholar] [CrossRef] [PubMed]
  326. Dutta, S.; Rittinger, K. Regulation of NOXO1 activity through reversible interactions with p22 and NOXA1. PLoS ONE 2010, 5, e10478. [Google Scholar] [CrossRef] [PubMed]
  327. Okur, H.; Kucukaydin, M.; Kose, K.; Kontas, O.; Dogam, P.; Kazez, A. Hypoxia-induced necrotizing enterocolitis in the immature rat: The role of lipid peroxidation and management by vitamin E. J. Pediatr. Surg. 1995, 30, 1416–1419. [Google Scholar] [CrossRef]
  328. Chan, K.L.; Hui, C.W.; Chan, K.W.; Fung, P.C.; Wo, J.Y.; Tipoe, G.; Tam, P.K. Revisiting ischemia and reperfusion injury as a possible cause of necrotizing enterocolitis: Role of nitric oxide and superoxide dismutase. J. Pediatr. Surg. 2002, 37, 828–834. [Google Scholar] [CrossRef] [PubMed]
  329. Wang, Z.; Li, S.; Cao, Y.; Tian, X.; Zeng, R.; Liao, D.F.; Cao, D. Oxidative Stress and Carbonyl Lesions in Ulcerative Colitis and Associated Colorectal Cancer. Oxid. Med. Cell. Longev. 2016, 2016, 9875298. [Google Scholar] [CrossRef] [PubMed]
  330. Cai, H.; Scott, E.; Kholghi, A.; Andreadi, C.; Rufini, A.; Karmokar, A.; Britton, R.G.; Horner-Glister, E.; Greaves, P.; Jawad, D.; et al. Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. Sci. Transl. Med. 2015, 7, 298ra117. [Google Scholar] [CrossRef] [PubMed]
  331. Zhu, W.; Qin, W.; Zhang, K.; Rottinghaus, G.E.; Chen, Y.C.; Kliethermes, B.; Sauter, E.R. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr. Cancer 2012, 64, 393–400. [Google Scholar] [CrossRef] [PubMed]
  332. Key, T.; Appleby, P.; Barnes, I.; Reeves, G.; Endogenous, H.; Breast Cancer Collaborative, G. Endogenous sex hormones and breast cancer in postmenopausal women: Reanalysis of nine prospective studies. J. Natl. Cancer Inst. 2002, 94, 606–616. [Google Scholar] [PubMed]
  333. Chow, H.H.; Garland, L.L.; Heckman-Stoddard, B.M.; Hsu, C.H.; Butler, V.D.; Cordova, C.A.; Chew, W.M.; Cornelison, T.L. A pilot clinical study of resveratrol in postmenopausal women with high body mass index: Effects on systemic sex steroid hormones. J. Transl. Med. 2014, 12, 223. [Google Scholar] [CrossRef] [PubMed]
  334. Renehan, A.G.; Zwahlen, M.; Minder, C.; O’Dwyer, S.T.; Shalet, S.M.; Egger, M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis. Lancet 2004, 363, 1346–1353. [Google Scholar] [CrossRef]
  335. Brown, V.A.; Patel, K.R.; Viskaduraki, M.; Crowell, J.A.; Perloff, M.; Booth, T.D.; Vasilinin, G.; Sen, A.; Schinas, A.M.; Piccirilli, G.; et al. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: Safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 2010, 70, 9003–9011. [Google Scholar] [CrossRef] [PubMed]
Figure 1. The chemical structure of two geometric isomers of resveratrol.
Figure 1. The chemical structure of two geometric isomers of resveratrol.
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Figure 2. A schematic diagram summarizing the potential mechanism(s) underlying the anticancer effects of resveratrol.
Figure 2. A schematic diagram summarizing the potential mechanism(s) underlying the anticancer effects of resveratrol.
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Table 1. In vivo anti-cancer effects of resveratrol.
Table 1. In vivo anti-cancer effects of resveratrol.
Cancer ModelAnimal ModelDoseOutcomeReferences
SkinDMBA/TPA model in female CD-1 mice1, 5, 10, 25 μmol topically twice/week for 18 weeksIncidence↓ Number of tumors per mouse↓[46]
Mouse xenograft models of A431 cells10, 20, 40 μg i.p. for 14 daysXenograft volume↓ Free radical scavenging Incidence↓ Number of tumors per mouse↓[198]
DMBA-initiated and TPA-promoted papillomas in female ICR mice85 nmol/L for 21 days; topical applicationPrevent onset of skin tumor[199]
DMBA/TPA model in CD-1 mice1, 5, 10, 25 μmol Twice/week, for 18 Wk; topical applicationSkin tumor incidence↓ Apoptosis↑; p53↑; Bax↑; cytochrome C↑; APAF↑; Bcl2↓[200]
DMBA-TPA–model in male Swiss albino mice50 μmol/mouse for 3–24 week; topical applicationInhibits photocarcinogenesis; Cox2↓; lipid peroxidation↓; ODC↓[201]
UVB-mediated photocarcinogenesis in female SKH-1 mice25 μmol/mouse; topical applicationDecrease hyperplasia; p53↑; Cox2↓; ODC↓; survivin↓ mRNA and protein[202]
UVB-induced skin hyperplasia in female SKH-1 mice10 μmol/mouse; 7 times, on alternate days; topical applicationSkin tumor incidence↓ ↑Survivin mRNA and protein; ↑ phospho-survivin; ↓Smac/DIABLO[203,204].
UVB-induced skin tumorigenesis in female SKH-1 mice25, 50 μmol/mouse; twice/week for 28 weeks; topical applicationSuppresses melanoma tumor growth[205]
C57Bl/6N mice transplanted with B16-BL6 melanoma cells50 mg/kg b.w.; i.p. for 19 days [206]
BreastSpontaneous mammary tumor in female FVB/N HER-2/neu mice4 μg/mouse/day in drinking water for 2 monthsOnset of tumorigenesis↓ Tumor volume↓ Multiplicity↓ Apoptosis↑[207]
Female athymic mice xenograft models of MDA-MB-231 cells25 mg/kg/day i.p. daily for 3 weeksTumor volume↓ TUNEL staining↓ Microvessel density↓[208]
Female Balb/c mice xenograft with cigarette smoke condensate-transformed, MCF-10A-Tr cells in mammary fat pad40 mg/kg/day orally for 30 daysTumor volume↓[209]
DMBA-induced mammary carcinogenesis in female Sprague-Dawley rats10 ppm mixed in diet; for 127 daysSuppressed tumor growth NF-κB↓;Cox2↓; MMP9↓[210]
DMBA-induced mammary carcinogenesis in female Sprague-Dawley rats100 mg/kg b.w. mixed in diet; for 25 weeksSuppressed tumor growth Cell proliferation↓ Apoptosis↑[211]
MNU-induced mammary tumorigenesis in female Sprague-Dawley rats100 mg/kg b.w. by oral gavage for 127 daysEstrogen modulation Reduces tumor growth[212]
MDA-MB-231 breast tumor xenograft model25 mg/kg b.w, by i.p., for 3 weeksInhibits tumor growth Apoptosis↑ Angiogenesis↓[208]
Female HER-2/neu transgenic mice model0.2 mg/kg b.w in drinking water for 2 monthsDelays the development and reduces the metastatic growth of spontaneous mammary tumors Apoptosis↑ ↓HER-2/neu mRNA and protein[207]
MDA-MB-231 breast tumor xenograft model in female athymic nu/nu mice5 and 25 mg/kg b.w., thrice a week by oral gavage for 117 days, In combination with quercetin and catechin retards the growth of tumor[213]
ProstateAthymic nude mice xenograft models of PC-3 cells30 mg/kg/day Thrice/week, total 6 weeksTumor volume↓ Cell proliferation↓ Apoptosis↑ Number of blood vessels↓[214]
Male nude mice xenograft models with Du145-EV-Luc or Du145-MTA1 shRNA-Luc in anterior prostate50 mg/kg/day i.p. daily 14 days after implantation, total 6 weeksTumor growth↓ Progression, local invasion↓ Spontaneous metastasis↓ Angiogenesis↓ Apoptosis↑[215]
Transgenic adenocarcinoma of mouse prostate (TRAMP) model625 mg/kg mixed in diet for 7–23 weeksER-β ↑; IGF-I ↑; ↓phospho-ERK-1;↓ERK-2[216]
Transgenic rat adenocarcinoma of prostate (TRAP) model50, 100 or 200 μg/ml in drinking water for 7 weeksApoptosis ↑; ↓AR; ↓GK11 mRNA[217]
LungFemale C57BL/6 mice xenograft models of LLC tumors0.6, 2.5 or 10 mg/kg/day i.p. daily for 21 daysTumor volume/weight↓ Metastasis to lung↓[218]
Nude mice xenograft models of A54915, 30 or 60 mg/kg i.v. daily for 15 daysTumor volume↓[219]
C57BL/6 mice implanted with Lewis lung carcinoma lung tumor model5 and 25 mg/kg, i.p. for 15 daysMetastasis↓ Angiogenesis↓[220]
C57BL/6 mice implanted with Lewis lung carcinoma lung tumor model20 mg/kg, i.p. for 17 daysAngiogenesis↓ Apoptosis ↑[221]
ColonDMH models in male Wistar rats8 mg/kg/day orally daily for 30 weeksIncidence↓, Tumor volume↓, Tumor burden/rat↓ Histopathological lesions DMH↓[222]
BP models in male ApcMin mice45 μg/kg/day orally, for 60 daysNumber of colon adenomas↓ Dysplasia occurrence↓[223]
AOM induced colon cancer in male F344 rats200 μg/kg b.w. in drinking waterBax↑; p21↑[224]
ApcMin/+ mice model0.01% in drinking water for 7 weeksReduce formation of tumor in small intestine cyclin D1 and D2↓[225]
ApcMin/+ mice model240 mg/kg b.w. mixed in diet for 10–14 weeksSuppress intestinal adenoma formation Cox1 and 2↓; PGE2↓[226]
LiverMale Donryu rats xenograft models of AH109A cells10, 50 ppm in diet for 20 daysTumor weight↓ Metastasis↓[227]
Male Wistar rats implanted with AH- 130 hepatoma cells1 mg/kg; 7 days; i.p.Tumor weight↓ Apoptosis↑ ↑cells at G2/M[228]
BALB/c mice implanted with H22 hepatoma cells500, 1000, 1500 mg/kg; 10 days; abdominal injectionImmunomodulatory activity↑[229]
BALB/c mice implanted with H22 hepatoma cells5, 10, 15 mg/kg; 10 days; abdominal injectionTumor volume↓ Apoptosis↑ cyclin B1↓; p34cdc2↓[230]
BALB/c mice implanted with H22 hepatoma cells5, 10, 15 mg/kg; 10 days; abdominal injectionSynergistic anti-tumor effect in combination with 5-FU; S-phase arrest[231]
Female BALB/c mice implanted with HepG2 cells15 mg/kg; every alternate day for 21 days; i.p.Tumor growth↓ Apoptosis↑ Caspase 3↑[232]
DENA-initiated GST-P-positive hepatic pre-neoplastic foci in male Sprague–Dawley rats15% (w/w) grape extract in diet; 11 weeksTumor growth↓ Lipid peroxidation↓ Fas ↓[233]
DENA-initiated and PB-promoted hepatocyte nodule formation in female Sprague–Dawley rats50, 100, 300 mg/kg; 20 weeks; dietTumor growth↓ Apoptosis↑ Cell proliferation↓ Bcl2↓; Bax↑[234]
↓: downregulated; ↑: upregulated; UVB: ultraviolet B; DMBA: 7,12-Dimethylbenz[a]anthracene; MNU: methyl-N-nitrosourea; AOM: azoxymethane; DENA: diethylnitrosamine; GST-P: glutathione S-transferase; PB: phenobarbital ; p53: tumor protein p53; Bax: Bcl-2-associated-X-protein; APAF: Apoptotic protease activating factor 1; Bcl2: B-cell lymphoma 2; Cox: cyclooxygenase; ODC: ornithine decarboxylase; Smac/DIABLO: Second mitochondriaderived activator of caspases /Diablo homolog; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; MMP9: matrix metalloproteinase nine; HER-2: human epidermal growth factor receptor 2; ER-β: estrogen receptor beta; IGF-I: insulin-like growth factor 1ERK: extracellular regulated kinase; AR: androgen receptor; GK11: glandular kallikrein 11; DMH: 1,2-dimethylhydrazine ; PGE2: prostaglandin E2; 5-FU: 5-fluorouracil.
Table 2. Selected clinical trials evaluating the effect of resveratrol in cancer patients.
Table 2. Selected clinical trials evaluating the effect of resveratrol in cancer patients.
ParticipantsResveratrol Formulation and DosagesOutcomeReferences
Colorectal cancer patients (n = 8)Grape powder (80 or 120 g/day) or Resveratrol (20 or 80 mg/day) for 2 weeksInhibition of Wnt target gene expression in normal colonic mucosa.[320]
Colorectal cancer patients (n = 20)Resveratrol (0.5 or 1g) for 8 daysReduction of Ki-67 levels by 5 and 7% in cancerous and normal tissue, respectively.[322]
Colorectal cancer patients with hepatic metastasis (n = 6)Micronized resveratrol (SRT5001, 5 g) for 14 daysDetection of resveratrol in hepatic tissue and increased (39%) content of cleaved caspase-3 in malignant hepatic tissue.[315]
Multiple myeloma patients (n = 24)Micronized resveratrol (SRT5001, 5 g) for 20 days in a 21 day cycle up to 12 cyclesUnacceptable safety profile and minimal efficacy in patients with relapsed/refractory multiple myeloma highlighting the risks of novel drug development in such populations.[316]
Biochemically recurrent prostate cancer patients (n = 14)Pulverized muscadine grape skin extract (MPX) 4000 mg/patientMPX was found to be safe and warrants further investigation in dose-evaluating phase II trial[323]
Benign prostate hyperplasis patients (n = 66)Two doses of resveratrol (150 mg or 1000 mg resveratrol daily) for 4 monthsSignificantly lowered the serum levels of androgens with no changes in prostate tumor growth.[324]

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