Next Article in Journal
Bothrops lanceolatus Bites: Guidelines for Severity Assessment and Emergent Management
Next Article in Special Issue
Phytochemicals in Cancer Prevention and Therapy: Truth or Dare?
Previous Article in Journal
Cytotoxic Necrotizing Factors (CNFs)−A Growing Toxin Family
Review

Curcumin―The Paradigm of a Multi-Target Natural Compound with Applications in Cancer Prevention and Treatment

Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, L-2540 Luxembourg, Luxembourg
*
Author to whom correspondence should be addressed.
Toxins 2010, 2(1), 128-162; https://doi.org/10.3390/toxins2010128
Received: 28 December 2009 / Revised: 11 January 2010 / Accepted: 12 January 2010 / Published: 21 January 2010

Abstract

As cancer is a multifactor disease, it may require treatment with compounds able to target multiple intracellular components. We summarize here how curcumin is able to modulate many components of intracellular signaling pathways implicated in inflammation, cell proliferation and invasion and to induce genetic modulations eventually leading to tumor cell death. Clinical applications of this natural compound were initially limited by its low solubility and bioavailability in both plasma and tissues but combination with adjuvant and delivery vehicles was reported to largely improve bio-availability of curcumin. Moreover, curcumin was reported to act in synergism with several natural compounds or synthetic agents commonly used in chemotherapy. Based on this, curcumin could thus be considered as a good candidate for cancer prevention and treatment when used alone or in combination with other conventional treatments.
Keywords: curcumin; cancer; inflammation; cell proliferation; genomic curcumin; cancer; inflammation; cell proliferation; genomic

1. Introduction

Most of the conventional chemotherapeutic agents used today were designed to hit a single intracellular target (e.g., Remicade® to counteract tumor necrosis factor, Avastin® to inhibit vascular endothelial growth factor). Unfortunately, the physiological and mechanistic deregulations responsible for cancer initiation and promotion implicate often hundreds of genes or signaling cascades so that it appears evident that multi-target drugs are requested to overcome complex human diseases such as cancer. Taking advantage of the multiple therapeutic effects observed after the use of natural compounds in traditional medicine, researchers started to evaluate the anti-tumor effect of natural compounds and subsequently tried to understand their mechanism of actions. By this way, they pointed out that curcumin, an active chemical component issued from the plant Curcuma longa, exhibits a broad range of activities due to its ability to affect multiple intracellular targets [1]. We will detail hereafter the different intracellular mechanisms affected by curcumin treatment and the resulting therapeutic applications potentially useful for the eradication of cancer.

2. Curcumin

Curcumin or diferuloylmethane, a polyphenolic molecule extracted from the rhizome of the plant Curcuma longa, is a yellow spice that enters into the composition of curry (Figure 1). This natural compound was used over centuries in Ayurvedic, Chinese and Hindu traditional medicine. Nowadays, it appears as a promising chemopreventive compound able to reverse, inhibit or prevent the development of cancer by inhibiting specific molecular signaling pathways involved in carcinogenesis [2,3,4,5]. Whereas clinical trials have already demonstrated the safety of curcumin even at high doses (12 g/day) [6,7,8,9,10], the clinical advancement of this promising natural compound is hampered by its poor water solubility and short biological half-life, resulting in low (micromolar rrange) bioavailability in both plasma and tissues [8,11,12] (Table 1).
In order to overcome these limitations, several approaches have been tested in vitro including the combination of curcumin with adjuvants (e.g., piperine), and the development of delivery vehicles consisting of liposomes, nanoparticules and phospholipid formulations of curcumin. We present in Table 1 the ongoing clinical trials involving curcumin in patients affected by cancer. In these trials, curcumin was mostly administrated alone or in combination with adjuvants (bioperine) or other natural compounds (quercetin, green tea and soybean extracts). Curcumin was also tested for its synergism with conventional treatments such as sulindac, capecitabine and celecoxib (Table 1). Completed clinical trials performed in patients affected by colorectal cancer [9,10,13,14] confirmed the different pharmacological criteria of curcumin cited previously and evaluated the effect of this natural compound on cyclooxygenase (COX-2), leukocytic M1G and gluthatione S transferase (GST) levels in patients.
In order to overcome these limitations, several approaches have been tested in vitro including the combination of curcumin with adjuvants (e.g., piperine), and the development of delivery vehicles consisting of liposomes, nanoparticules and phospholipid formulations of curcumin. We present in Table 1 the ongoing clinical trials involving curcumin in patients affected by cancer. In these trials, curcumin was mostly administrated alone or in combination with adjuvants (bioperine) or other natural compounds (quercetin, green tea and soybean extracts). Curcumin was also tested for its synergism with conventional treatments such as sulindac, capecitabine and celecoxib (Table 1). Completed clinical trials performed in patients affected by colorectal cancer [9,10,13,14] confirmed the different pharmacological criteria of curcumin cited previously and evaluated the effect of this natural compound on cyclooxygenase (COX-2), leukocytic M1G and gluthatione S transferase (GST) levels in patients.

2.1. Curcumin analogues and structure related activity

The comparison between the effect of curcumin and its naturally occurring analogues including its demethoxy derivatives (demethoxycurcumin, bisdemethoxycurcumin) and its active hydrogenated metabolites (tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin) (Figure 1) pointed out possible structure-activity relationships.
Table 1. Ongoing clinical trials involving curcumin in patients affected by cancer.
Table 1. Ongoing clinical trials involving curcumin in patients affected by cancer.
StatusTrial nameDiseaseTreatment appliedClinical phase study
CompletedCurcumin (Diferuloylmethane Derivative) With or Without Bioperine in Patients With Multiple MyelomaMultiple MyelomaCurcumin; Bioperinend
RecruitingCurcumin With Pre-Operative Capecitabine and Radiation Therapy Followed by Surgery for Rectal CancerRectal CancerRadiation: Radiotherapy; Capecitabine; Curcumin; PlaceboPhase II
RecruitingCurcumin for Prevention of Oral Mucositis in Children ChemotherapyChemotherapy Induced MucositisCurcumin liquid extractPhase III
RecruitingCurcumin in preventing colorectal cancer in patients undergoing colorectal endoscopy and colorectal surgeryColorectal cancerCurcumin Phase I
Endoscopy, surgery
RecruitingTrial of Curcumin in Advanced Pancreatic CancerAdenocarcinoma; Pancreatic NeoplasmsCurcuminPhase II
Active, not recruitingCurcumin in Preventing Colon Cancer in Smokers With Aberrant Crypt FociColorectal Cancer; Precancerous/Nonmalignant ConditionDietary Supplement: curcuminPhase II
Not yet recruitingBio-Availability of a New Liquid Tumeric ExtractHealthyliquid tumeric/curcumin extractPhase I
RecruitingPilot Study of Curcumin Formulation and Ashwagandha Extract in Advanced OsteosarcomaOsteosarcomaDietary Supplement: Curcumin powder, Ashwagandha extractPhase I and II
RecruitingGemcitabine With Curcumin for Pancreatic CancerPancreatic CancerCurcumin (+gemcitabine)Phase II
Not yet recruitingPhase III Trial of Gemcitabine, Curcumin and Celebrex in Patients With Metastatic Colon CancerColon NeoplasmCelecoxib; curcuminPhase III
SuspendedCurcumin for Treatment of Intestinal Adenomas in Familial Adenomatous Polyposis (FAP)Familial Adenomatous PolyposisDietary Supplement: curcumin; Dietary Supplement: placeboPhase II
RecruitingCurcumin for Treatment of Intestinal Adenomas in Familial Adenomatous Polyposis (FAP)Familial Adenomatous PolyposisCurcuminnd
TerminatedUse of Curcumin in the Lower Gastrointestinal Tract in Familial Adenomatous Polyposis PatientsFamilial Adenomatous PolyposiscurcuminPhase II
RecruitingPhase III Trial of Gemcitabine, Curcumin and Celebrex in Patients With Advance or Inoperable Pancreatic CancerPancreatic CancerGemcitabine; Curcumin; CelebrexPhase III
CompletedCurcumin for the Prevention of Colon CancerColorectal CancerDietary Supplement: curcuminPhase I
TerminatedThe Effects of Curcuminoids on Aberrant Crypt Foci in the Human ColonAberrant Crypt Focisulindac; curcuminnd
Not yet recruitingA Nutritional Supplement Capsule Containing Curcumin, Green Tea Extract, Polygonum Cuspidatum Extract, and Soybean Extract in Healthy ParticipantsHealthy, no Evidence of DiseaseDietary Supplement: curcumin/green tea extract/Polygonum cuspidatum extract/soybean extract capsulend
SuspendedSulindac and Plant Compounds in Preventing Colon CancerColorectal CancerDietary Supplement: curcumin, rutinnd
Drug : quercetin, sulindac
RecruitingCurcumin for the Chemoprevention of Colorectal CancerAdenomatous PolypsCurcuminoidsPhase II
Not yet recruitingTrial of Curcumin in Cutaneous T-cell Lymphoma PatientsCutaneous T-Cell LymphomaDietary Supplement: Curcumin (Turmeric)Phase II
The table was generated by using the registry of federally and privately supported clinical trials conducted in the United States and around the world (http://clinicaltrials.gov). Nd: non defined.
It was reported that the high anti-inflammatory and anti-tumoral potential of curcuminoids are related to low level of hydrogenation and high level of methoxylation but also to the high level of unsaturation of the diketone moiety [15]. On the other hand, the radical scavenging potential of the curcuminoids was linked to the number of ortho-methoxy substitutions and to the level of hydrogenation of the heptadiene moiety of curcumin [16,17]. Indeed, glycosylation of curcumin aromatic ring provides a more water-soluble compound with a greater kinetic stability and a good therapeutic index [18].
Figure 1. Chemical structure of curcuminoids. Curcumin (A), curcumin demethoxy derivatives (demethoxycurcumin and bisdemethoxycurcumin) (B) and hydrogenated curcumin metabolites (tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin).
Figure 1. Chemical structure of curcuminoids. Curcumin (A), curcumin demethoxy derivatives (demethoxycurcumin and bisdemethoxycurcumin) (B) and hydrogenated curcumin metabolites (tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin).
Toxins 02 00128 g001

2.2. Curcumin formulations

Due to the multiple therapeutic potential of curcumin, various formulations were tested in order to enhance its bioavailability and to bring this natural compound to the forefront of therapeutic agents [19]. On one hand, formulation of curcumin in nanoparticles [20,21], liposomes [22,23], micelles [24] and phospholipid complexes decreases its hydrophobicity and increase its circulation time, its permeability through membrane barriers, its solubility as well as its resistance to metabolic stress [11]. On the other hand, the use of an adjuvant like piperine isolated from black pepper (that inhibits UGTs and p450s) [25], quercetin derived from soy beans (that inhibits sulfotransferases) and genistein (that inhibits alcohol dehydrogenase) counteracts detoxification enzymes implicated in curcumin metabolism. This leads to the increase of curcumin absorption, serum concentration and subsequently to the increase of curcumin bioavailability [19,26].

3. Signaling Pathways Affected by Curcumin Treatment

As cancer is a multifactorial disease, it requires treatment of multiple molecular targets compounds linked to chemoprevention, treatment and drug resistance often observed after chemotherapy.
In an attempt to improve understanding of the pleiotropic targets of curcumin, different studies have been performed so far by microarray gene expression profiling in various cancer types (Table 2). In fact, this technical approach allows to assess simultaneously the expression pattern of a high number of genes at the RNA level [27,28]. Curcumin could effectively be considered a good candidate for cancer prevention when used alone and for cancer treatment in combination with other conventional therapies as it is able to target multiple signaling pathways implicated in this disease [29,30] (Figure 2).
Figure 2. Modulation of multiple molecular targets by curcumin in cancer cells. These modulations lead to initiation and progression steps of carcinogenesis but also to cancer cell death. Arrows represent induction/activation whereas blunt-ended lines represented inhibition/repression.
Figure 2. Modulation of multiple molecular targets by curcumin in cancer cells. These modulations lead to initiation and progression steps of carcinogenesis but also to cancer cell death. Arrows represent induction/activation whereas blunt-ended lines represented inhibition/repression.
Toxins 02 00128 g002
Table 2. Evaluation by gene expression profiling of the molecular targets of curcumin in cancer cells.
Table 2. Evaluation by gene expression profiling of the molecular targets of curcumin in cancer cells.
PlatformBiological SystemResultsReference
Oligonucleotide arrayshuman K562 chronic myelogenous leukemia cell lineRegulation of cell cycle, JAK-STAT signaling pathway and heat shock related genes by curcumin in TNF-treated K562 cells. [27]
Oligonucleotide arrayshuman BxPC-3 pancreatic carcinoma cell lineCurcumin alters miRNA expression in human pancreatic cells by up-regulating miRNA-22 and down-regulating miRNA-199a*. [28]
Superarrayhuman SK-N-MC neuroblastoma cell lineCurcumin is a potent radiosensitizer that inhibits growth of human neuroblastoma cells and downregulates radiation-induced pro-survival factors implicating NF-kB transcription factor. [29]
Affymetrixhuman MDA-MB-231 estrogen-negative breast cancer cell line Curcumin is able to downregulate the expression levels of inflammatory cytokines CXCL1 and -2 in breast cancer implicating NF-κB transcription factor. [30]
cDNA arrayshuman CL 1-5 lung adenocarcinoma cell lineCurcumin supresses cancer cell proliferation and invasion in lung carcinoma cells by downregulating the expression of MT1-MMP, NCAM, TOPO-I TOPO- II and AXL and the activity of MMP2 and NF-κB. Additionally expression of different HSP family members was induced by curcumin. [31]
cDNA arrayshuman SW620 and Caco-2 colon adenocarcinoma cell linesCurcumin induces a G2-M cell cycle arrest in epithelial colorectal carcinoma by modulating genes implicated in cell cycle progression [32]
Affymetrixwild-type C57BL/6J mice, Nrf2 knockout C57BL/6J/Nrf2(-/-) miceNovel curcumin-regulated Nrf2-dependent genes implicated in the chemopreventive effects of curcumin in mice liver and intestine were identified. These genes are implicated in ubiquitination, proteolysis, electron transport, detoxification, transport, apoptosis, cell cycle, cell adhesion as well as kinase/phosphatase and transcription factor activity. [33]
Affymetrixhuman MDA-1986 oral squamous carcinoma cell lineSeveral putative, novel molecular targets of curcumin were identified, amongst which ATF3, a contributor to the proapoptotic effects of this compound. [34]
Illuminahuman HF4.9 follicular lymphoma cell lineCurcumin is able to downregulate CXCR4 and CD20 in follicular lymphoma cells. These genes play an important role in pathogenesis of follicular lymphoma. [35]
cDNA arrayshuman RKO adenocarcinoma cell lineCurcumin downregulates p53 target genes at the RNA level. This effect is mediated by disrupting the native conformation of wild-type p53 protein. [36]
cDNA arrayshuman HT29 colon adenocarcinoma cell lineConfirmation of the known effects of curcumin as cell cycle arrest in G2/M arrest and induction of phase-II genes). Extension of the existing knowledge on these physiological effects and detection of new mechanistic impact such as its effects on tubulin genes and the differential expression of p16(INK4), p53 and RB1. [37]
Affymetrixrat C6 glioma cell lineFour primary pathways are targeted by curcumin in neuroglial cells, including oxydative stress, cell cycle control, DNA transcription and metabolism. Additionally new target genes related to oxidative stress as well as cell cycle control were identified. [38]
Affymetrix, Superarrayhuman LNCap androgen-responsive prostate adenocarcinoma cell line, human C42B androgen non-responsive prostate adenocarcinoma cell line (derived from LNCap cell line)Oxidative stress response was identified as the major pathway involved in curcumin induced biological responses in prostate cancer cells. Additionally curcumin suppresses androgen receptor in androgen responsive and refractory cells. [39]

3.1. Curcumin and inflammation

Over the past decades, experimental studies were performed to understand the intracellular mechanisms targeted by curcumin that implicated in the promising therapeutic potential of this natural compound used since centuries in traditional medicine. Aggarwal and coworkers firstly described curcumin as a potent modulator of inflammatory cell signaling [31]. This finding was promising as inflammation is highly involved in the promotion step of tumorigenesis, through the induction of survival, proliferation, invasion, angiogenesis and metastasis [32]. Aggarwal pointed out that this effect on inflammation was mainly due to inhibition of the nuclear factor-kB (NF-κB) signaling pathway [33]. Subsequent studies revealed that this natural compound acts on several components of this pathway. In fact, curcumin was shown to suppress the activation of IkBa kinase (IKK), the phosphorylation and degradation of IkBa and the subsequent phophorylation and nuclear translocation of the p65 subunit in several cancer and premalignant cell types [34,35,36,37,38,39,40]. This prevention of NF-κB activation is also related to the ability of curcumin to inhibit the proteasome function [41,42,43]. Such an inhibition of NF-κB was also induced after treatment with curcumin analogs such as demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and 3,5-bis(2-flurobenzylidene)-piperidin-4-one (EF24) [16,44]. Similar results were also observed in primary cells issued from multiple myeloma patients [45] and in patients with advanced pancreatic cancer [46]. It is important to notify that NF-κB regulates the expression of more the 450 genes implicated in all main signaling pathways [47] such as tumor cell proliferation (cyclins), invasion potential (matrix metalloproteinases (MMP), adhesion molecules), angiogenesis (vascular endothelial growth factor (VEGF)) [48] but also growth factors (epidermal growth factor (EGF), tumor necrosis factor (TNFa)) and most of the anti-apoptotic genes (Bcl-2 and X linked inhibitor of apoptosis (XIAP)) [49] as well as numerous oncogenes [50]. The down-regulation of the NF-κB pathway by curcumin could thus impact other related signaling pathways as demonstrated in several studies [51,52,53,54,55] and provide opportunities for both prevention and treatment [56].
In addition to its impact on NF-κB, curcumin also affects other molecular events implicated in inflammation and subsequent tumor promotion [31,57] such as inflammatory cytokines (TNFa, interleukines IL-1, IL-6 and IL-8) [58,59], inflammatory transcription factors (STATs), and inflammatory enzymes (Cyclooxygenase (COX)-2, 5-lipoxygenase (LOX)) [60].
It is reported in the literature that persistent activation of STATs also mediates tumor-promoting inflammation through their collaboration with other transcription factors [31,61,62]. Again, the inhibition of this transcription factor represents a promising tool both for prevention and therapy. We reported that curcumin alone inhibits STATs expression, especially the decrease of nuclear STAT-3, -5a and -5b, without affecting neither STAT1 nor the phosphorylation state of STAT1, -3 or -5 in human chronic K562 leukemia cells. When used as a pre-treatment, curcumin inhibits interferon-gamma-induced phosphorylation of nuclear STAT1 and -3 [63,64]. Similar suppression of STAT3 activation was also observed in Hodgkin’s lymphoma [52], T-cell leukemia [65], head and neck squamous cell carcinoma [66], multiple myeloma cells [52,67] and in CD138+ cells derived from multiple myeloma patients [45] following curcumin treatment but also after treatment with curcumin analogs such as GO-Y030 [68], FLLL1 and FLLL12 [69] or a curcumin-phospholipid complex [70]. The interferon-a-induced activation of STAT1 was also inhibited by curcumin in human lung A549 carcinoma and melanoma cells [71]. This inhibition of STAT1 as well as the inhibition of NF-κB were suggested to be implicated in the inhibition of COX-2, an important reactive-oxygen-generating enzymes implicated in inflammatory processes [55,72,73,74]. In fact, it was reported that curcumin is a potent inhibitor of COX-2 in several cancer types [37,73,75,76,77,78,79,80,81]. Moreover, studies performed on mononuclear cells from peripheral blood of patients with pancreatic cancer [46] and on oral premalignant cells [40] reported an inhibition of COX-2 expression after curcumin treatment. More recently, fluorocurcumin, a curcumin analog presenting a higher bioavailability than curcumin, was also shown to down-regulate NF-κB and prostaglandin (PG)E2 level so that it was suggested to be a potential agent against COX-2 overexpressing tumors [82]. All of these in vitro as well as preclinical studies suggested that targeting components of the inflammatory pathways provide good opportunities for prevention and therapy of cancer [56].

3.2. Impact of curcumin on tumor cell proliferation and invasion

Carcinogenesis is a multistage process with three successive steps, initiation, promotion and progression. This process is often linked to oxidative stress, chronic inflammation and hormonal imbalance. The chemopreventive effect of curcumin is mainly based on its effectiveness to inhibit tumorigenesis through the decrease of cancer cell proliferation.
A way for curcumin to counteract cancer cell proliferation consists in the arrest of the cell cycle. This antiproliferative effect was observed in several cancer cell types (prostate, lung, breast and head and neck cancer but also lymphoma and leukemia). In fact, curcumin induces the expression of cyclin-dependent kinase (CDK) inhibitors p16, p21 and p27, and inhibits the expression of cyclin E and cyclin D1 as well as the hyperphosphorylation of retinoblastoma (Rb) protein. This leads to the disruption of cell cycle and to the death of cells by apoptosis [83,84,85].
The modulation of cyclins could be related to the impact of curcumin on the Wingless (Wnt) signaling pathway [86,87], especially through the modulation of the b-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) as observed in osteosarcoma [88], colon cancer cells [89,90], breast stem and cancer cells [91,92]. The observed decrease of the b-catenin/Tcf transcriptional activity was due to the decrease of the nuclear level of expression of b-catenin and Tcf-4 [89]. Similar decrease of b-catenin expression was also shown to be responsible of the inhibition of intestinal tumor growth in an animal model of familial adenomatous polyposis [93]. Gene expression profiling by microarray revealed that curcumin was also able to attenuate the expression of Frizzled-1, a Wnt receptor [94]. Demethoxycurcumin and bisdemethoxycurcumin, two curcumin analogs, were also reported to decrease the b-catenin transcriptional activity with a comparable potency as curcumin in colorectal cancer, through the down-regulation of p300, which is a positive regulator of the Wnt signaling pathway. As the tetrahydrocurcumin metabolite exhibits a much lesser impact on the Wnt pathway, it was suggested that the conjugated bonds in the central seven-carbon chain of curcuminoids are essential for the anti-proliferative activity of curcuminoids [95].
Dysregulations of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways were also shown to play an important role in cancer cell growth and survival. Thus the targeting of these pathways may provide new anti-cancer strategies [96,97]. Curcumin was reported to be a good inhibitor of phosphoinositol (PI)3/Akt/mammalian target of rapamycin (mTOR) signaling pathway through the modulation of their expression and phosphorylation in a panel of cancer cell lines derived from leukemia [55,98], cervical cancer [99], colorectal carcinoma [100], renal carcinoma [101], breast cancer [102], Ewing’s sarcoma [103], prostate cancer cells and xenografts [104,105,106,107]. This leads to cell death by apoptosis and to the down-regulation of downstream effector proteins and genes such as p53, NF-κB and eukaryotic initiation factors (eIFs) which play an important role in the initiation of protein synthesis [108,109]. Such an inhibition of PI3/Akt/NF-κB signaling pathway by curcumin was also suggested to be implicated in the down-regulation of the expression of P-glycoprotein (P-gp) implicated in the multidrug resistance (mdr) 1b gene-mediated multidrug resistance [110].
Curcumin analogues such as FLLL11, FLLL12 and 4-hydroxy-3-methybenzoic acid methyl ester (HMBME) were also described as good inhibitors of cell proliferation of breast and prostate cancer though the modulation of PI3/Akt/ mTOR signaling [69,100,111].
The proliferation of solid tumors is also highly linked to their potential to establish metastasis and invade surrounding tissues. This phenomenon is based on the ability of tumor cells to produce growth factors such as EGF, VEGF and MMPs.
Matrix metalloproteinases (MMPs) play a major role in this phenomenon by mediating neovascularization, endothelial cell migration and tube formation [112]. The alteration of MMP-1, membrane type-1 matrix metalloproteinase (MT1-MMP), MMP-2, MMP-9 expression was observed after curcumin treatment in vitro and in vivo in melanoma [113], prostate [114,115], lung [116] and breast cancer cells [117,118].
Over-expression of epidermal growth factor receptor (EGFR) is highly implicated in cancer cell proliferation [119,120]. Curcumin was shown to down-regulate the EGFR expression in pancreatic and lung adenocarcinoma expressing COX-2 [81]. This natural compound also inhibits the EGFR intrinsic kinase activity in human epidermoid carcinoma [121], breast [122], prostate [123,124] and colon cancer cells [125]. This decrease of EGFR expression and activity could be subsequent to the inhibition of the ligand-induced activation of EGFR [126], to the peroxisome proliferator-activated receptor-g (PPAR-g) activation [127], to the suppression of EGFR phosphorylation [128] or to the decrease of the early growth factor-1 (Egr-1) transcriptional activity [129] observed after curcumin treatment. A similar decrease of the EGFR expression level was also observed in estrogen receptor negative breast cancer treated with derivatives of curcumin issued from the replacement of phenyl group of cyclohexanone derived curcumin by heterocyclic rings [122].
Curcumin also appears to be a direct in vitro and in vivo inhibitor of VEGF and fibroblast growth factor (FGF) [48,77,116,130,131,132,133,134], that are usually elevated in many human cancer and that correlate with enhanced microvessel density and metastatic spread. The molecular mechanisms, implicated in curcumin-inhibition of angiogenesis, consist also in the down regulation of the expression of pro-angiogenic components such as angiopoietin 1 and 2 genes, Kinase Domain Region (KDR) [131] and cell surface expression of vascular adhesion molecules (VCAM-1) [135]. Curcumin and its metabolite tetrahydrocurcumin were also reported to decrease the microvascular dilatation, tortuosity and hyper-permeability in hepatocellular carcinoma implanted in nude mouse [136].

3.3. Curcumin and genomic modulations

Telomeres are specialized heterochromatic structures localized at the end of human chromosomes. They consist of tandem repeats that play structural and functional roles and allow maintaining genome stability. In healthy cells, telomeres are shortened during each cell division so that the cells stop replicating once the telomeres become too short. In contrast, the majority of solid tumors and leukemia acquire elevated telomerase activity to overcome such limitations ensuring thus their immortality and unlimited proliferative potential through the bypass of senescence [137,138]. Telomerase inhibition emerges thus as an attractive target for cancer therapy [139,140]. Treatment of cancer cells with curcumin revealed that this natural compound inhibits telomerase activity by down-regulating the human telomerase reverse transcriptase (hTERT), the catalytic core of telomerase which leads thus to the suppression of cell viability and to the induction of apoptosis [141,142,143,144,145]. Recent findings suggest that such a down-regulation of hTERT could be explained by a decrease of the association of hTERT and p23, a component of the molecular chaperone complex Hsp90-p23 that normally interacts with the rate-limiting catalytic subunit of telomerase [146].
In order to specifically target telomerase, Kappor et al., have taken advantage of the RNA subunit conformation of telomerase. They linked a tetraglycine conjugate of curcumin to an 11-mer DNA sequence complementary to a telomerase RNA sequence. Treatment of oral KB cancer cells with such a construct leads to the a significant reduction of cancer cell growth [147].
In addition to genetic alterations, cancer development and progression are also linked to epigenetic modifications [148], which consist mainly in DNA methylation and posttranslational histone modifications (acetylation, methylation, ubiquitylation, phosphorylation and sumoylation). DNA methylation is mediated by DNA methyltransferases (DNMTs). Aberrant hypermethylation of promoter CpG islands of tumor suppressor genes results in their transcriptional silencing and tumor survival [149]. Curcumin as well as tetrahydrocurcumin were reported to block covalently the catalytic thiolate of the C1226 of DNMT1 leading thus to DNA hypomethylation and suggesting a subsequent death of tumor cells [150].
On the other hand, the level of histone acetylation, resulting from the balance of histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, plays a crucial role in chromatin remodeling and in the regulation of gene transcription [151]. The impact of curcumin on these implicated epigenetic mechanisms was evaluated and revealed that this natural compound is able to induce histone hypoacetylation by blocking the HAT activity in vitro and in vivo without affecting HDAC [152]. In fact, curcumin was reported to be a potent and specific inhibitor of p300/CREB Binding Protein (CBP) histone acetyltransferase activity in several cancer types by promoting their proteasomal degradation, whereas its tetrahydrocurcumin metabolite does not affect p300 [153,154,155]. Molecular docking carried out for the human HDAC8 enzyme, pointed out that curcumin could also be considered as a potent HDAC inhibitor [156] and other studies showed that it can also significantly decrease the amount of HDAC1 and HDAC3 [157].
More recently, several studies pointed out that deregulation of microRNAs, a category on small noncoding RNAs that function as genes regulators, were also involved in tumorigenesis and related to epigenetics alterations. In fact, the microRNA network is implicated in the regulation of many basic cellular processes such as proliferation, differentiation and cell death [158,159,160,161,162]. Evidence has been provided that dietary compounds such as curcumin could exert their chemopreventive effect through the modulation of miRNAs expression [163]. Indeed, curcumin was reported to alter miRNA expression by up-regulating miRNA-22 and down-regulating miRNA-199a* in human pancreatic cells [164]. On the other hand, this natural compound was also able to up-regulate the expression of miRNA-15a and miRNA-16 which leads to the reduction of the expression of the anti-apoptotic Bcl-2 gene [165].

4. Mechanisms of Cell Death Induced by Curcumin

Curcumin is most often described to induce tumor cell death through the well-described apoptosis process [166]. However, tumor cell resistance to apoptosis appears frequently and is associated with poor prognosis and resistance to cancer treatment [167]. Fortunately, other types of mechanism leading to cell death (e.g., autophagy, mitotic catastrophe) are also induced by curcumin in order to compensate this lack of induction of cell death mechanisms.

4.1. Apoptosis

Apoptosis is a tightly regulated mechanism of cell death that can be initiated by intracellular stress signals and extracellular ligands following curcumin treatment in several cancer types [166,168]. The intrinsic induction of apoptosis is triggered in response to cellular signals including stress and DNA damage. Curcumin was reported to induce the up-regulation of pro-apoptotic proteins from the Bcl-2 family (Bim, Bax, Bak, Puma and Noxa) and the down-regulation of anti-apoptotic proteins (XIAP, Bcl-2, Bcl-xL) [101,105]. This leads to the opening of mitochondrial permeability transition pores, the release of cytochrome c, the activation of the apoptosome (caspase-9/apaf-1/cytochrome c) and the subsequent cleavage of caspase-3, -6 and -7, Poly (ADP-ribose) polymerase (PARP) and finally to the death of tumor cells [169,170,171]. Pre-clinical studies pointed out that curcumin has similar pro-apoptotic effect on primary chronic lymphocytic leukemia B cells but that this effect is inhibited in the presence of stromal cells. In order to overcome this protective effect mediated by stromal cells, curcumin needs to be administered simultaneously with epigallocatechin-3 gallate (EGCG) [172].
On the other hand, apoptosis may also be induced by the extrinsic pathway at the cell surface through the activation of cell membrane receptors (Fas, TRAIL) [173,174,175]. This pathway leads to the assembly of the death- inducing signaling complex (DISC) containing Fas, FAD and caspase-8 and -10. The extrinsic pathway converges then to the intrinsic one by the induction of Bid cleavage, the subsequent release of cytochrome c and the activation of the cascade of caspases.
This induction of cell death by apoptosis after curcumin or curcumin analogs treatment [176] supports the idea of their possible implication for cancer therapy [16,177].

4.2. Mitotic catastrophe

Mitotic catastrophe (MC) is a type of cell death resulting from aberrant mitosis. In fact, this process results from a combination of deficient cell-cycle checkpoints (DNA structure and spindle assembly checkpoints) and cellular damage. Moreover, it has been reported that the intrinsic mitochondrial apoptotic machinery (chromatin condensation, mitochondrial release of proapoptotic proteins, caspase-2 activation and DNA degradation) is highly implicated in the execution of mitotic catastrophe, which occurs at the metaphase level, in a p53 independent manner [178,179]. This type of mitosis leads to the formation of large non-viable cells with several micronuclei and uncondensed chromosomes [179,180]. The disruption of mitotic spindle structure and the appearance of micronucleation after curcumin treatment were firstly described in MCF-7 human breast cancer cells and were related to curcumin-induced cell cycle arrest in G2/M [181]. Mitotic catastrophe was also a way for curcumin to overcome the resistance of tumor cells to apoptosis. In the case of curcumin, the induction of MC was related to the inhibition of survivin, a modulator of cell division and apoptosis in cancer [182,183]. Moreover, curcumin-induced cytotoxicity observed in a panel of oesophageal cancer cell lines after 24h of treatment was associated to MC induction related to an accumulation of the mitotic regulator cyclin B1 and of poly-ubiquitinated proteins [184]. Other publications underline the fact that curcumin metabolites, derivatives and products of degradation were unable to induce G2/M cell cycle arrest and MC compared to the original curcumin compound [185,186].
Mitotic catastrophe induction should be considered for clinical approaches, as a correlation was found between poor prognosis of treatment and inability of cells to induce MC. Moreover an increase of MC induction could compensate impaired induction of apoptosis [167].

4.3. Autophagy

Autophagy is a highly regulated process characterized by sequestration of bulk cytoplasm, long-lived proteins and cellular organelles in double-membrane vesicles (autophagosomes), which are subsequently degraded in lysosomes. The final role of autophagy as a tumor suppressor or a protector of cancer cells from anti-cancer therapy is still under investigation [187,188,189]. In the case of curcumin, it was recently reported that this natural compound suppresses the growth of malignant gliomas in vitro and in vivo through cell cycle arrest in G2/M transition phase and induction of autophagy. This phenomenon has been associated to the inhibition of the Akt/mTOR kinase and to the activation of the extracellular signal-regulated kinases (ERK) 1/2 and to the increase of LC-3 II expression [190,191]. Such an induction of autophagy was also observed concomitantly with mitotic catastrophe in oesophageal cancer after curcumin treatment [184].

5. Curcumin Synergistic Effect in Combination with Other Natural or Chemotherapeutic Compounds

As described above, curcumin is a multi-target natural chemopreventive compound by itself. In addition to its high chemopreventive potential, this natural compound can act synergistically with other natural compounds or other kinds of therapy (radiotherapy, chemotherapy and hormonotherapy).

5.1. Synergism with natural compounds

Curcumin was reported to have a synergistic effect with genistein, a natural compound derived from soy beans. When combined, they are able to reduce the proliferation of the human breast MCF-7 oestrogen-positive cells induced by environmental pesticides [192]. Moreover, combination of curcumin with 1,25-dihydroxyvitamin D3 (calcitrol) treatment, a well known inducer of monocytic differentiation, was able to stimulate monocytic differentiation of the human promyelocytic HL-60 cells [193] and to abolish resistance of calcitrol-differentiated HL60 cells to DNA damage-induced apoptosis by activating other cell signaling pathways leading to cell death [194]. Diet containing both curcumin and omega-3 fatty acids (fish oil diet) leads to the prevention and treatment of pancreatic tumor xenografts through the down-regulation of the expression and activity of iNOS, COX-2 and 5-LOX and up-regulation of p21 [78]. Coadministration of curcumin with embellin, a natural benzoquinone derived from Embelia ribes berries, prevents lipid peroxidation, histological alterations and oxidative tissue damage occurring usually during chemically-induced hepatocarcinogenesis in Wistar albino rats [195]. An additive inhibitory effect on cell proliferation was also observed in human prostate cancer PC-3 cells in vitro and in vivo in human PC-3 xenografts mice treated concomitantly with curcumin and b-phenylethyl isothiocyanate (PEITC), a natural compound issued from cruciferous vegetables. This inhibitory effect was related to the suppression of epidermal growth factor (EGFR), Akt and PI3K phosphorylations and the inhibition of the NF-κB signaling pathway [128,196]. A similar cascade of events was also pointed out following the combination of curcumin and resveratrol in vitro in HCT116 colon cancer cells and in vivo in colon cancer xenografts [197]. Synergistic interactions of curcumin with epigallocatechin-3-gallate (EGCG), a polyphenolic compound found in green tea leads to the reduction of their respective dose index in normal, premalignant and malignant human oral epithelial cells [198]. In the case of chronic lymphocytic leukemia cells (CLL), synergism between EGCG and curcumin allows to overcome the stromal-mediated protection of the CLL cells in the case of sequential therapy. By this way, EGCG sensitizes the cells to curcumin effects and is able to increase strongly cell death in leukemic cells [172]. Curcumin administrated in combination with piperine, an alkaloid from black pepper, inhibits breast stem cell self-renewal without inducing toxicity to differentiated cells. This inhibitory effect is mediated by the inhibition of mammosphere formation and Wnt signaling pathway, but without causing toxicity to differentiated cells [91].
A clinical approach revealed that the combination of curcumin with quercetin, a plant derived flavonoid, reduces the number and size of ileal and adenomas in patients with familial adenomatous polyposis without appreciable toxicity [199]. Most of the natural compounds cited above to have synergestic effect with curcumin in vitro or in vivo are included in ongoing clinical trials in patients affected by cancer.

5.2. Synergism with conventional therapy

Due to frequent failure of conventional treatment alone (radiotherapy, chemotherapy and hormonotherapy), novel clinical strategies, based on the combination of different treatments together or in conjunction with chemopreventive agents, are emerging.
The combination of curcumin with radiation enhances significantly the radiation-induced clonogenic inhibition and induces cell death by apoptosis. This combination of treatment reduces the TNFa-mediated NF-κB activity, alters the Bax/Bcl-2 ratio and activates cytochrome c, caspase-9 and caspase-3 in PC-3 prostate cancer cells [200], but also in colorectal cancer cells [53]. Pretreatment of cervical carcinoma cells results in a significant dose-dependent radiosensitization of these cells. This involves an increase of reactive oxygen species (ROS) and extracellular signal-regulated kinase (ERK) 1/2 activation [201]. Altogether these data suggest that curcumin can be considered as a potent radiosensitizer in prostate and cervical cancer.
Several studies have also been performed in order to evaluate the potential synergistic activity of curcumin in combination with synthetic agents commonly used in chemotherapy. We will first focus on the combination of curcumin with chemotherapeutic agents from natural origin and currently used in clinic such as Taxol® (paclitaxel), derived from Taxus brevifolia. Curcumin was shown to potentiate the effect of paclitaxel-mediated chemotherapy in advanced breast cancer in vitro and in vivo and is able to inhibit lung metastasis. Such a sensitization of taxol-induced cell death by curcumin was also observed in cervical HeLa cancer cells. In both case, the potentiation of chemotherapy by curcumin was related to the down-regulation of NF-κB and serine/threonine Akt pathways, to the suppression of cyclooxygenase 2 (COX-2) and matrix metalloproteinase-9 (MMP-9) but also to the activation of caspases and cytochrome c release [117,202,203]. On the other hand, curcumin appears to be a good adjuvant to enhance the induction of apoptosis and the subsequent chemotherapeutic efficacy of vinorelbine for the treatment of advanced non-small lung H520 carcinoma cells [204] and of celecoxib, a well known COX-2 inhibitor, in pancreatic adenocarcinoma cells [205,206]. This synergism of curcumin and celecoxib is responsible for the down-regulation of the COX-2 signaling pathway. Such a reduction of COX-2 is also observed in human colon cancer HT-29 cell lines when curcumin is associated with the antimetabolite 5-fluorouracil (5-FU) chemotherapeutic agent [207]. The combination of curcumin and 5-FU was also reported for the eradication of human gastric adenocarcinoma cells through the induction of cell cycle arrest in G2/M transition phase [208]. Furthermore, curcumin is able to potentiate the antiproliferative effect of 5-FU associated with oxaliplatin or oxoplatin alone and to stimulate cell death by apoptosis through the attenuation of epidermal growth factors (EGF) and insuline-like growth factor (IGF) signaling pathways in colon cancer HCT-116 and HT-29 cells [209,210].
In addition to its ability to enhance the antitumoral effect of conventional chemotherapy, curcumin is also able to circumvent chemoresistance. Resistance to conventional chemotherapy often appears in the case of treatment with platinium (Pt) drugs such as cisplatin and oxaliplatin [211,212]. Several reports revealed that combination of curcumin with Pt drugs treatment inhibits the growth of cancer cells by modulating EGF and IGF receptors expression and by inducing G2/M cell cycle arrest through the modulation of Akt and p38 MAPK [209,210,213,214]. This combination also leads to the induction of cancer cell death by apoptosis through the increase of p53 tumor suppressor gene expression, through the proteasomal degradation of Bcl-2 mediating cisplatin resistance and through the reduction of interleukin-6 production [215,216]. In the case of colon cancer, the emergence of a subset of self-renewing cells, called cancer stem cells (CSCs), is highly implicated in the failure of oxaliplatin treatment. Treatment of oxaliplatin resistant CSCs cells with curcumin results in a marked reduction of CSCs cells accompanied by alterations of the level of DNA methyltransferase 1 [217]. These findings underline the fact that curcumin is able to increase the sensitivity of resistant cancer cells to Platinium drugs and to prevent the emergence of chemoresistant colon cancer cells due to the enrichment of cancer stem cells. Sung et al., showed that curcumin overcomes chemoresistance and potentiates the effect of thalidomide and bortezomib by down-regulating NF-κB and its target genes (e.g., cyclin D1, Bcl-xL, Bcl-2, XIAP, survivin and VEGF) in human multiple myeloma in vitro and in vivo [218]. More recently, curcumin was also found to potentiate the anti-tumor effect of gemcitabine, another pyrimidine antimetabolite, by suppressing proliferative and angiogenic biomarkers and by modulating the NF-κB signaling pathway in vitro in human bladder cancer 253JBV cells and in vivo in an orthotopic human bladder cancer [134]. Similar results were observed after combination of curcumin with capecitabine in the case of advanced metastatic colorectal cancer in an orthotopic mouse model. This combination was also highly effective in suppressing acites and distant metastasis in other organs [77].
Venkatesan et al. also reported that curcumin is able to attenuate the myocardial toxicity usually observed after adriamycin (doxorubicin) treatment of Wistar rats. In fact, such a pre-treatment with curcumin decreases the level of creatinine kinase and lactate deshydrogenase as well as lipid peroxidation and it increases the level of endogenous antioxidants in order to counteract the side effects of anthracycline chemotherapeutic agents [219]. Such combination of treatment could thus limit free radical-mediated organ injury normally observed after adriamycin treatment.
Curcumin, alone or in combination with docetaxel, was also shown to be highly potent in mice with multidrug-resistant tumors, by decreasing both proliferation, microvessel density and by increasing tumor cell apoptosis [48]. Recently, the results of a phase I dose escalation trial including fourteen patients with advanced or metastatic breast cancer pointed out that curcumin could be used in combination with docetaxel. This study allows to determine the maximal tolerated dose (6 mg/mL curcumin for seven consecutive days every three weeks in combination with a standard dose of docetaxel) as well as their toxicity, safety and effects on tumor marker [220]. Thanks to the encouraging data obtained by clinical trial, a comparative phase II clinical trial study is now under investigation.
Curcumin also appeared to be a good candidate to sensitize prostate cancer cells for TRAIL-mediated immunotherapy. TNFa related apoptosis-inducing ligand (TRAIL) is an inducer of apoptosis in many cancer cells and is an attractive cytokine for the treatment of advanced cancers including prostate cancer. Although prostate cancer cells (DU145, PC-3 and LNCaP) are mostly resistant to TRAIL, they can be sensitized with curcumin to TRAIL-induced apoptosis. This combination induces the inhibition of constitutively active NF-κB, DNA fragmentation, the cleavage of pro-caspase-3, pro-caspase-8 and pro-caspase-9, as well as the truncation of Bid and cytochrome c release. It also leads to the inhibition of the anti-apoptotic proteins Bcl-2, Bcl-xL and XIAP [38,105,221,222,223]. These results were confirmed in vivo by pre-clinical studies performed in PC-3 xenografts [224] and in TRAIL-resistant LNCaP xenografts [225].

6. The “Dark Side” of Curcumin

All of the previous reported findings have underlined the pharmacologically safety and biological effectiveness of curcumin and analogs. However it appeared that many of the anti-cancer effects of curcumin observed in vitro cannot be achieved in vivo or in patients mainly due to its low bioavailability outside the gastrointestinal tract after oral administration [9,226]. Moreover, several studies also pointed out that curcumin can exhibit toxicity and carcinogenic effects [12]. In a 2-year study performed on rodents fed with curcumin, an equivocal evidence of curcumin carcinogenic activity was reported as they observed an increased incidence of hepatocellular and clitoral gland adenoma as well as carcinomas of the small intestine, due to curcumin ingestion [227]. Curcumin also appeared responsible for the promotion of lung tumor multiplicity and its progression to later stages in transgenic mouse model expressing the human Ki-rasG12C allele and affected by lung cancer [228]. These negative effects of curcumin were suggested to be mediated by the presence of a,b-unsaturated ketone in its chemical structure that is responsible for the inactivation of the tumor suppressor p53 [229] and the production of ROS [230]. It also implicates its iron chelator potential [231]. Other groups revealed that curcumin could also induce chromosome aberrations [232] and DNA alterations [233], which are both highly implicated in carcinogenesis. Moreover, under specific conditions, curcumin could also be toxic and can alter the efficiency of conventional chemotherapy and radiotherapy [230]. In fact, it has been reported that curcumin inhibits camptothecin-, mechlorethamine-, and doxorubicin-induced apoptosis in human breast cancer in vitro by up to 70% and that it also inhibits the cyclophosphamide-induced tumor regression and apoptosis in in vivo models in a time and dose dependent manner. It was suggested that this inhibition of chemotherapy-induced apoptosis by curcumin happened through the inhibition of ROS generation and blockade of JNK function after curcumin treatment [234]. All of these findings lead to the conclusion that the balance between risk and benefit of curcumin should be taken into account before any clinical use for cancer prevention or therapy.

7. Conclusions

In this review we have summarized the major intracellular components targeted by curcumin treatment. All of these findings reinforce the idea that curcumin could be considered as a potent natural compound both for prevention and treatment of multifactorial disease such as cancer. However, more translational research and clinical trials with either native or formulated curcumin or in combination with compounds already approved for conventional therapies are needed to better understand the benefit-risk profile of curcumin before putting this natural compound in the forefront of clinical cancer therapy. With this in mind, numerous other natural compounds initially used, as curcumin, in traditional cooking or medicine, are now under investigations in order to discover other multipotent natural molecules that could be used in cancer prevention or therapy.

Acknowledgements

MHT and SE were supported by Télévie grants (Fonds National de la Recherche Scientifique, Belgium). M. Diederich’s research at the Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC) is financially supported by “Recherche Cancer et Sang” foundation, by «Recherches Scientifiques Luxembourg» asbl, by «Een Häerz fir Kriibskrank Kanner» association, the Action Lions “Vaincre le Cancer” Luxembourg, The Fonds National de la Recherche Luxembourg, Televie Luxembourg and the Foundation for Scientific Cooperation between Germany and Luxemburg for additional support. Further support was received from the European Union (ITN “RedCat” 215009 and Interreg IVa project “Corena”).

References

  1. Lin, J.K. Molecular targets of curcumin. Adv. Exp. Med. Biol. 2007, 595, 227–243. [Google Scholar] [PubMed]
  2. Aggarwal, B.B.; Bhatt, I.D.; Ichikawa, H.; Ahn, K.S.; Sethi, G.; Sandur, S.K.; Sundaram, C.; Seeram, N.; Shishodia, S. Curcumin: Biological and Medicinal properties. In Turmeric: The genus Curcuma; CRC Press: New York, NY, USA, 2007. [Google Scholar]
  3. Goel, A.; Kunnumakkara, A.B.; Aggarwal, B.B. Curcumin as "Curecumin": From kitchen to clinic. Biochem. Pharmacol. 2008, 75, 787–809. [Google Scholar] [PubMed]
  4. Hatcher, H.; Planalp, R.; Cho, J.; Torti, F.M.; Torti, S.V. Curcumin: From ancient medicine to current clinical trials. Cell. Mol. Life Sci. 2008, 65, 1631–1652. [Google Scholar] [PubMed]
  5. Thangapazham, R.L.; Sharma, A.; Maheshwari, R.K. Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J. 2006, 8, E443–449. [Google Scholar] [PubMed]
  6. Lao, C.D.; Ruffin, M.T. IV.; Normolle, D.; Heath, D.D.; Murray, S.I.; Bailey, J.M.; Boggs, M.E.; Crowell, J.; Rock, C.L.; Brenner, D.E. Dose escalation of a curcuminoid formulation. BMC Complement. Altern. Med. 2006, 6, 10. [Google Scholar] [PubMed]
  7. Chainani-Wu, N. Safety and anti-inflammatory activity of curcumin: A component of tumeric (Curcuma longa). J. Altern. Complement. Med. 2003, 9, 161–168. [Google Scholar] [PubMed]
  8. Cheng, A.L.; Hsu, C.H.; Lin, J.K.; Hsu, M.M.; Ho, Y.F.; Shen, T.S.; Ko, J.Y.; Lin, J.T.; Lin, B.R.; Ming-Shiang, W.; Yu, H.S.; Jee, S.H.; Chen, G.S.; Chen, T.M.; Chen, C.A.; Lai, M.K.; Pu, Y.S.; Pan, M.H.; Wang, Y.J.; Tsai, C.C.; Hsieh, C.Y. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001, 21, 2895–2900. [Google Scholar] [PubMed]
  9. Sharma, R.A.; Euden, S.A.; Platton, S.L.; Cooke, D.N.; Shafayat, A.; Hewitt, H.R.; Marczylo, T.H.; Morgan, B.; Hemingway, D.; Plummer, S.M.; Pirmohamed, M.; Gescher, A.J.; Steward, W. P. Phase I clinical trial of oral curcumin: Biomarkers of systemic activity and compliance. Clin. Cancer Res. 2004, 10, 6847–6854. [Google Scholar] [PubMed]
  10. Sharma, R.A.; McLelland, H.R.; Hill, K.A.; Ireson, C.R.; Euden, S.A.; Manson, M.M.; Pirmohamed, M.; Marnett, L.J.; Gescher, A.J.; Steward, W.P. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res. 2001, 7, 1894–1900. [Google Scholar] [PubMed]
  11. Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: Problems and promises. Mol. Pharm. 2007, 4, 807–818. [Google Scholar] [PubMed]
  12. Burgos-Moron, E.; Calderon-Montano, J.M.; Salvador, J.; Robles, A.; Lopez-Lazaro, M. The dark side of curcumin. Int. J. Cancer 2009, 126, 1771–1775. [Google Scholar] [CrossRef]
  13. Garcea, G.; Berry, D.P.; Jones, D.J.; Singh, R.; Dennison, A.R.; Farmer, P.B.; Sharma, R.A.; Steward, W.P.; Gescher, A.J. Consumption of the putative chemopreventive agent curcumin by cancer patients: Assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidem. Biomarker. Prev. 2005, 14, 120–125. [Google Scholar]
  14. Plummer, S.M.; Hill, K.A.; Festing, M.F.; Steward, W.P.; Gescher, A.J.; Sharma, R.A. Clinical development of leukocyte cyclooxygenase 2 activity as a systemic biomarker for cancer chemopreventive agents. Cancer Epidem. Biomarker. Prev. 2001, 10, 1295–1299. [Google Scholar]
  15. Sugiyama, Y.; Kawakishi, S.; Osawa, T. Involvement of the beta-diketone moiety in the antioxidative mechanism of tetrahydrocurcumin. Biochem. Pharmacol. 1996, 52, 519–525. [Google Scholar] [PubMed]
  16. Sandur, S.K.; Pandey, M.K.; Sung, B.; Ahn, K.S.; Murakami, A.; Sethi, G.; Limtrakul, P.; Badmaev, V.; Aggarwal, B.B. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis 2007, 28, 1765–1773. [Google Scholar] [PubMed]
  17. Somparn, P.; Phisalaphong, C.; Nakornchai, S.; Unchern, S.; Morales, N.P. Comparative antioxidant activities of curcumin and its demethoxy and hydrogenated derivatives. Biol. Pharm. Bull. 2007, 30, 74–78. [Google Scholar] [PubMed]
  18. Ferrari, E.; Lazzari, S.; Marverti, G.; Pignedoli, F.; Spagnolo, F.; Saladini, M. Synthesis, cytotoxic and combined cDDP activity of new stable curcumin derivative. Bioorg. Med. Chem. 2009, 17, 3043–3052. [Google Scholar] [PubMed]
  19. Anand, P.; Thomas, S.G.; Kunnumakkara, A.B.; Sundaram, C.; Harikumar, K.B.; Sung, B.; Tharakan, S.T.; Misra, K.; Priyadarsini, I.K.; Rajasekharan, K.N.; Aggarwal, B.B. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem. Pharmacol. 2008, 76, 1590–1611. [Google Scholar] [PubMed]
  20. Anand, P.; Nair, H.B.; Sung, B.; Kunnumakkara, A.B.; Yadav, V.R.; Tekmal, R.R.; Aggarwal, B.B. Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo. Biochem. Pharmacol. 2010, 79, 330–338. [Google Scholar] [PubMed]
  21. Bisht, S.; Feldmann, G.; Soni, S.; Ravi, R.; Karikar, C.; Maitra, A. Polymeric nanoparticle-encapsulated curcumin ("nanocurcumin"): A novel strategy for human cancer therapy. J. Nanobiotechnol. 2007, 5, 3. [Google Scholar]
  22. Narayanan, N.K.; Nargi, D.; Randolph, C.; Narayanan, B.A. Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. Int. J. Cancer 2009, 125, 1–8. [Google Scholar] [PubMed]
  23. Thangapazham, R.L.; Puri, A.; Tele, S.; Blumenthal, R.; Maheshwari, R.K. Evaluation of a nanotechnology-based carrier for delivery of curcumin in prostate cancer cells. Int. J. Oncol. 2008, 32, 1119–1123. [Google Scholar] [PubMed]
  24. Lapenna, S.; Bilia, A.R.; Morris, G.A.; Nilsson, M. Novel artemisinin and curcumin micellar formulations: Drug solubility studies by NMR spectroscopy. J. Pharm. Sci. 2009, 98, 3666–3675. [Google Scholar] [PubMed]
  25. Shaikh, J.; Ankola, D.D.; Beniwal, V.; Singh, D.; Kumar, M.N. Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. Eur. J. Pharm. Sci. 2009, 37, 223–230. [Google Scholar] [PubMed]
  26. Shoba, G.; Joy, D.; Joseph, T.; Majeed, M.; Rajendran, R.; Srinivas, P.S. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998, 64, 353–356. [Google Scholar] [PubMed]
  27. Lockhart, D.J.; Dong, H.; Byrne, M.C.; Follettie, M.T.; Gallo, M.V.; Chee, M.S.; Mittmann, M.; Wang, C.; Kobayashi, M.; Horton, H.; Brown, E.L. Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat. Biotechnol. 1996, 14, 1675–1680. [Google Scholar] [PubMed]
  28. Schena, M.; Shalon, D.; Davis, R.W.; Brown, P.O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 1995, 270, 467–470. [Google Scholar] [PubMed]
  29. Aggarwal, B.B.; Takada, Y.; Oommen, O.V. From chemoprevention to chemotherapy: Common targets and common goals. Expert Opin. Investig. Drugs 2004, 13, 1327–1338. [Google Scholar] [PubMed]
  30. Sarkar, F.H.; Li, Y. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics. Canc. Treat. Rev. 2009, 35, 597–607. [Google Scholar] [CrossRef]
  31. Aggarwal, B.B.; Gehlot, P. Inflammation and cancer: How friendly is the relationship for cancer patients? Curr. Opin. Pharmacol. 2009, 9, 351–369. [Google Scholar] [CrossRef] [PubMed]
  32. Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867. [Google Scholar] [PubMed]
  33. Singh, S.; Aggarwal, B.B. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J. Biol. Chem. 1995, 270, 24995–25000. [Google Scholar] [PubMed]
  34. Jobin, C.; Bradham, C.A.; Russo, M.P.; Juma, B.; Narula, A.S.; Brenner, D.A.; Sartor, R.B. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J. Immunol. 1999, 163, 3474–3483. [Google Scholar] [PubMed]
  35. Bharti, A.C.; Donato, N.; Singh, S.; Aggarwal, B.B. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 2003, 101, 1053–1062. [Google Scholar] [PubMed]
  36. Siwak, D.R.; Shishodia, S.; Aggarwal, B.B.; Kurzrock, R. Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer 2005, 104, 879–890. [Google Scholar] [PubMed]
  37. Shishodia, S.; Potdar, P.; Gairola, C.G.; Aggarwal, B.B. Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: Correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis 2003, 24, 1269–1279. [Google Scholar] [PubMed]
  38. Deeb, D.; Jiang, H.; Gao, X.; Al-Holou, S.; Danyluk, A.L.; Dulchavsky, S.A.; Gautam, S.C. Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1-6-heptadine-3,5-dione; C21H20O6] sensitizes human prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L-induced apoptosis by suppressing nuclear factor-kappaB via inhibition of the prosurvival Akt signaling pathway. J. Pharmacol. Exp. Ther. 2007, 321, 616–625. [Google Scholar] [CrossRef] [PubMed]
  39. Dhandapani, K.M.; Mahesh, V.B.; Brann, D.W. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J. Neurochem. 2007, 102, 522–538. [Google Scholar] [PubMed]
  40. Sharma, C.; Kaur, J.; Shishodia, S.; Aggarwal, B.B.; Ralhan, R. Curcumin down regulates smokeless tobacco-induced NF-kappaB activation and COX-2 expression in human oral premalignant and cancer cells. Toxicology 2006, 228, 1–15. [Google Scholar] [PubMed]
  41. Milacic, V.; Banerjee, S.; Landis-Piwowar, K.R.; Sarkar, F.H.; Majumdar, A.P.; Dou, Q.P. Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. Cancer Res. 2008, 68, 7283–7292. [Google Scholar] [PubMed]
  42. Yang, H.; Landis-Piwowar, K.R.; Chen, D.; Milacic, V.; Dou, Q.P. Natural compounds with proteasome inhibitory activity for cancer prevention and treatment. Curr. Protein Pept. Sci. 2008, 9, 227–239. [Google Scholar] [PubMed]
  43. Landis-Piwowar, K.R.; Milacic, V.; Chen, D.; Yang, H.; Zhao, Y.; Chan, T.H.; Yan, B.; Dou, Q.P. The proteasome as a potential target for novel anticancer drugs and chemosensitizers. Drug Resist. Update. 2006, 9, 263–273. [Google Scholar]
  44. Kasinski, A.L.; Du, Y.; Thomas, S.L.; Zhao, J.; Sun, S.Y.; Khuri, F.R.; Wang, C.Y.; Shoji, M.; Sun, A.; Snyder, J.P.; Liotta, D.; Fu, H. Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin. Mol. Pharmacol. 2008, 74, 654–661. [Google Scholar] [PubMed]
  45. Bharti, A.C.; Shishodia, S.; Reuben, J.M.; Weber, D.; Alexanian, R.; Raj-Vadhan, S.; Estrov, Z.; Talpaz, M.; Aggarwal, B.B. Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis. Blood 2004, 103, 3175–3184. [Google Scholar] [PubMed]
  46. Dhillon, N.; Aggarwal, B.B.; Newman, R.A.; Wolff, R.A.; Kunnumakkara, A.B.; Abbruzzese, J.L.; Ng, C.S.; Badmaev, V.; Kurzrock, R. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 2008, 14, 4491–4499. [Google Scholar] [PubMed]
  47. Karin, M.; Greten, F.R. NF-kappaB: Linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 2005, 5, 749–759. [Google Scholar] [PubMed]
  48. Lin, Y.G.; Kunnumakkara, A.B.; Nair, A.; Merritt, W.M.; Han, L.Y.; Armaiz-Pena, G.N.; Kamat, A.A.; Spannuth, W.A.; Gershenson, D.M.; Lutgendorf, S.K.; Aggarwal, B.B.; Sood, A.K. Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin. Cancer Res. 2007, 13, 3423–3430. [Google Scholar] [PubMed]
  49. Notarbartolo, M.; Poma, P.; Perri, D.; Dusonchet, L.; Cervello, M.; D'Alessandro, N. Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression. Cancer Lett. 2005, 224, 53–65. [Google Scholar] [PubMed]
  50. Chen, F.; Castranova, V.; Shi, X. New insights into the role of nuclear factor-kappaB in cell growth regulation. Am. J. Pathol. 2001, 159, 387–397. [Google Scholar] [PubMed]
  51. Marin, Y.E.; Wall, B.A.; Wang, S.; Namkoong, J.; Martino, J.J.; Suh, J.; Lee, H.J.; Rabson, A.B.; Yang, C.S.; Chen, S.; Ryu, J.H. Curcumin downregulates the constitutive activity of NF-kappaB and induces apoptosis in novel mouse melanoma cells. Melanoma Res. 2007, 17, 274–283. [Google Scholar] [PubMed]
  52. Mackenzie, G.G.; Queisser, N.; Wolfson, M.L.; Fraga, C.G.; Adamo, A.M.; Oteiza, P.I. Curcumin induces cell-arrest and apoptosis in association with the inhibition of constitutively active NF-kappaB and STAT3 pathways in Hodgkin's lymphoma cells. Int. J. Cancer 2008, 123, 56–65. [Google Scholar] [PubMed]
  53. Sandur, S.K.; Deorukhkar, A.; Pandey, M.K.; Pabon, A.M.; Shentu, S.; Guha, S.; Aggarwal, B.B.; Krishnan, S. Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity. Int. J. Radiat. Oncol. Biol. Phys. 2009, 75, 534–542. [Google Scholar] [PubMed]
  54. Mukhopadhyay, A.; Bueso-Ramos, C.; Chatterjee, D.; Pantazis, P.; Aggarwal, B.B. Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene 2001, 20, 7597–7609. [Google Scholar] [PubMed]
  55. Aggarwal, S.; Ichikawa, H.; Takada, Y.; Sandur, S.K.; Shishodia, S.; Aggarwal, B.B. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol. Pharmacol. 2006, 69, 195–206. [Google Scholar] [PubMed]
  56. 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] [PubMed]
  57. Sandur, S.K.; Ichikawa, H.; Pandey, M.K.; Kunnumakkara, A.B.; Sung, B.; Sethi, G.; Aggarwal, B.B. Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radic. Biol. Med. 2007, 43, 568–580. [Google Scholar] [PubMed]
  58. Wang, S.L.; Li, Y.; Wen, Y.; Chen, Y.F.; Na, L.X.; Li, S.T.; Sun, C.H. Curcumin, a potential inhibitor of up-regulation of TNF-alpha and IL-6 induced by palmitate in 3T3-L1 adipocytes through NF-kappaB and JNK pathway. Biomed. Environ. Sci. 2009, 22, 32–39. [Google Scholar] [PubMed]
  59. Moon, D.O.; Jin, C.Y.; Lee, J.D.; Choi, Y.H.; Ahn, S.C.; Lee, C.M.; Jeong, S.C.; Park, Y.M.; Kim, G.Y. Curcumin decreases binding of Shiga-like toxin-1B on human intestinal epithelial cell line HT29 stimulated with TNF-alpha and IL-1beta: Suppression of p38, JNK and NF-kappaB p65 as potential targets. Biol. Pharm. Bull. 2006, 29, 1470–1475. [Google Scholar] [PubMed]
  60. Menon, V.P.; Sudheer, A.R. Antioxidant and anti-inflammatory properties of curcumin. Adv. Exp. Med. Biol. 2007, 595, 105–125. [Google Scholar] [PubMed]
  61. 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] [PubMed]
  62. Aggarwal, B.B.; Kunnumakkara, A.B.; Harikumar, K.B.; Gupta, S.R.; Tharakan, S.T.; Koca, C.; Dey, S.; Sung, B. Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship? Ann. NY Acad. Sci. 1171, 59–76. [Google Scholar]
  63. Blasius, R.; Reuter, S.; Henry, E.; Dicato, M.; Diederich, M. Curcumin regulates signal transducer and activator of transcription (STAT) expression in K562 cells. Biochem. Pharmacol. 2006, 72, 1547–1554. [Google Scholar] [PubMed]
  64. Teiten, M.H.; Eifes, S.; Reuter, S.; Duvoix, A.; Dicato, M.; Diederich, M. Gene expression profiling related to anti-inflammatory properties of curcumin in K562 leukemia cells. Ann. NY Acad. Sci. 2009, 1171, 391–398. [Google Scholar]
  65. Rajasingh, J.; Raikwar, H.P.; Muthian, G.; Johnson, C.; Bright, J.J. Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia. Biochem. Biophys. Res. Commun. 2006, 340, 359–368. [Google Scholar] [PubMed]
  66. Chakravarti, N.; Myers, J.N.; Aggarwal, B.B. Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane). Int. J. Cancer 2006, 119, 1268–1275. [Google Scholar] [PubMed]
  67. Bharti, A.C.; Donato, N.; Aggarwal, B.B. Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J. Immunol. 2003, 171, 3863–3871. [Google Scholar] [PubMed]
  68. Hutzen, B.; Friedman, L.; Sobo, M.; Lin, L.; Cen, L.; de Angelis, S.; Yamakoshi, H.; Shibata, H.; Iwabuchi, Y.; Lin, J. Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas. Int. J. Oncol. 2009, 35, 867–872. [Google Scholar] [PubMed]
  69. Lin, L.; Hutzen, B.; Ball, S.; Foust, E.; Sobo, M.; Deangelis, S.; Pandit, B.; Friedman, L.; Li, C.; Li, P.K.; Fuchs, J.; Lin, J. New curcumin analogues exhibit enhanced growth-suppressive activity and inhibit AKT and signal transducer and activator of transcription 3 phosphorylation in breast and prostate cancer cells. Cancer Sci. 2009, 100, 1719–1727. [Google Scholar] [PubMed]
  70. Cucuzza, L.S.; Motta, M.; Miretti, S.; Accornero, P.; Baratta, M. Curcuminoid-phospholipid complex induces apoptosis in mammary epithelial cells by STAT-3 signaling. Exp. Mol. Med. 2008, 40, 647–657. [Google Scholar] [PubMed]
  71. Bill, M.A.; Bakan, C.; Benson, D.M., Jr.; Fuchs, J.; Young, G.; Lesinski, G.B. Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines. Mol. Cancer Ther. 2009, 8, 2726–2735. [Google Scholar] [PubMed]
  72. Lee, J.; Jung, H.H.; Im, Y.H.; Kim, J.H.; Park, J.O.; Kim, K.; Kim, W.S.; Ahn, J.S.; Jung, C.W.; Park, Y.S.; Kang, W.K.; Park, K. Interferon-alpha resistance can be reversed by inhibition of IFN-alpha-induced COX-2 expression potentially via STAT1 activation in A549 cells. Oncol. Rep. 2006, 15, 1541–1549. [Google Scholar] [PubMed]
  73. Lee, K.W.; Kim, J.H.; Lee, H.J.; Surh, Y.J. Curcumin inhibits phorbol ester-induced up-regulation of cyclooxygenase-2 and matrix metalloproteinase-9 by blocking ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A human breast epithelial cells. Antioxid. Redox Signal. 2005, 7, 1612–1620. [Google Scholar] [PubMed]
  74. Plummer, S.M.; Holloway, K.A.; Manson, M.M.; Munks, R.J.; Kaptein, A.; Farrow, S.; Howells, L. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene 1999, 18, 6013–6020. [Google Scholar] [PubMed]
  75. Atsumi, T.; Murakami, Y.; Shibuya, K.; Tonosaki, K.; Fujisawa, S. Induction of cytotoxicity and apoptosis and inhibition of cyclooxygenase-2 gene expression, by curcumin and its analog, alpha-diisoeugenol. Anticancer Res. 2005, 25, 4029–4036. [Google Scholar] [PubMed]
  76. Rao, C.V. Regulation of COX and LOX by curcumin. Adv. Exp. Med. Biol. 2007, 595, 213–226. [Google Scholar] [PubMed]
  77. Kunnumakkara, A.B.; Diagaradjane, P.; Anand, P.; Kuzhuvelil, H.B.; Deorukhkar, A.; Gelovani, J.; Guha, S.; Krishnan, S.; Aggarwal, B.B. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model. Int. J. Cancer 2009, 125, 2187–2197. [Google Scholar] [PubMed]
  78. Swamy, M.V.; Citineni, B.; Patlolla, J.M.; Mohammed, A.; Zhang, Y.; Rao, C.V. Prevention and treatment of pancreatic cancer by curcumin in combination with omega-3 fatty acids. Nutr. Cancer 2008, 60, 81–89. [Google Scholar] [PubMed]
  79. Hong, J.; Bose, M.; Ju, J.; Ryu, J.H.; Chen, X.; Sang, S.; Lee, M. J.; Yang, C.S. Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivatives: Effects on cytosolic phospholipase A(2), cyclooxygenases and 5-lipoxygenase. Carcinogenesis 2004, 25, 1671–1679. [Google Scholar] [PubMed]
  80. Goel, A.; Boland, C.R.; Chauhan, D.P. Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett. 2001, 172, 111–118. [Google Scholar] [PubMed]
  81. Lev-Ari, S.; Starr, A.; Vexler, A.; Karaush, V.; Loew, V.; Greif, J.; Fenig, E.; Aderka, D.; Ben-Yosef, R. Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition of Erk1/2 activity. Anticancer Res. 2006, 26, 4423–4430. [Google Scholar] [PubMed]
  82. Padhye, S.; Banerjee, S.; Chavan, D.; Pandye, S.; Swamy, K.V.; Ali, S.; Li, J.; Dou, Q.P.; Sarkar, F.H. Fluorocurcumins as cyclooxygenase-2 inhibitor: Molecular docking, pharmacokinetics and tissue distribution in mice. Pharm. Res. 2009, 26, 2438–2445. [Google Scholar] [PubMed]
  83. Mukhopadhyay, A.; Banerjee, S.; Stafford, L.J.; Xia, C.; Liu, M.; Aggarwal, B.B. Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene 2002, 21, 8852–8861. [Google Scholar] [PubMed]
  84. Srivastava, R.K.; Chen, Q.; Siddiqui, I.; Sarva, K.; Shankar, S. Linkage of curcumin-induced cell cycle arrest and apoptosis by cyclin-dependent kinase inhibitor p21(/WAF1/CIP1). Cell Cycle 2007, 6, 2953–2961. [Google Scholar] [PubMed]
  85. Aggarwal, B.B.; Banerjee, S.; Bharadwaj, U.; Sung, B.; Shishodia, S.; Sethi, G. Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. Biochem. Pharmacol. 2007, 73, 1024–1032. [Google Scholar] [PubMed]
  86. Janssens, N.; Janicot, M.; Perera, T. The Wnt-dependent signaling pathways as target in oncology drug discovery. Invest. New Drug. 2006, 24, 263–280. [Google Scholar]
  87. Narayan, S. Curcumin, a multi-functional chemopreventive agent, blocks growth of colon cancer cells by targeting beta-catenin-mediated transactivation and cell-cell adhesion pathway. J. Mol. Histol. 2004, 35, 301–307. [Google Scholar] [PubMed]
  88. Leow, P.; Tian, Q.; Ong, Z.; Yang, Z.; Ee, P. Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/beta-catenin antagonists against human osteosarcoma cells. Invest. New Drug. 2009, 28, 766–782. [Google Scholar] [CrossRef]
  89. Park, C.H.; Hahm, E.R.; Park, S.; Kim, H.K.; Yang, C.H. The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling. FEBS Lett. 2005, 579, 2965–2971. [Google Scholar] [PubMed]
  90. Jaiswal, A.S.; Marlow, B.P.; Gupta, N.; Narayan, S. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002, 21, 8414–8427. [Google Scholar] [PubMed]
  91. Kakarala, M.; Brenner, D.E.; Korkaya, H.; Cheng, C.; Tazi, K.; Ginestier, C.; Liu, S.; Dontu, G.; Wicha, M.S. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res. Treat. 2009. [Google Scholar]
  92. Prasad, C.P.; Rath, G.; Mathur, S.; Bhatnagar, D.; Ralhan, R. Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem. Biol. Interact. 2009, 181, 263–271. [Google Scholar] [PubMed]
  93. Mahmoud, N.N.; Carothers, A.M.; Grunberger, D.; Bilinski, R.T.; Churchill, M.R.; Martucci, C.; Newmark, H.L.; Bertagnolli, M.M. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis 2000, 21, 921–927. [Google Scholar] [PubMed]
  94. Yan, C.; Jamaluddin, M.S.; Aggarwal, B.; Myers, J.; Boyd, D.D. Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol. Cancer Ther. 2005, 4, 233–241. [Google Scholar] [PubMed]
  95. Ryu, M.J.; Cho, M.; Song, J.Y.; Yun, Y.S.; Choi, I.W.; Kim, D.E.; Park, B.S.; Oh, S. Natural derivatives of curcumin attenuate the Wnt/beta-catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem. Biophys. Res. Commun. 2008, 377, 1304–1308. [Google Scholar] [PubMed]
  96. Chen, Y.L.; Law, P.Y.; Loh, H.H. Inhibition of PI3K/Akt signaling: An emerging paradigm for targeted cancer therapy. Curr. Med. Chem. Anticancer Agents 2005, 5, 575–589. [Google Scholar] [PubMed]
  97. Chang, F.; Lee, J.T.; Navolanic, P.M.; Steelman, L.S.; Shelton, J.G.; Blalock, W.L.; Franklin, R.A.; McCubrey, J.A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia 2003, 17, 590–603. [Google Scholar] [PubMed]
  98. Hussain, A.R.; Al-Rasheed, M.; Manogaran, P.S.; Al-Hussein, K.A.; Platanias, L.C.; Al Kuraya, K.; Uddin, S. Curcumin induces apoptosis via inhibition of PI3'-kinase/AKT pathway in acute T cell leukemias. Apoptosis 2006, 11, 245–254. [Google Scholar] [PubMed]
  99. Beevers, C.S.; Li, F.; Liu, L.; Huang, S. Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Int. J. Cancer 2006, 119, 757–764. [Google Scholar] [PubMed]
  100. Johnson, S.M.; Gulhati, P.; Arrieta, I.; Wang, X.; Uchida, T.; Gao, T.; Evers, B.M. Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res. 2009, 29, 3185–3190. [Google Scholar] [PubMed]
  101. Woo, J.H.; Kim, Y.H.; Choi, Y.J.; Kim, D.G.; Lee, K.S.; Bae, J.H.; Min, D.S.; Chang, J.S.; Jeong, Y.J.; Lee, Y.H.; Park, J.W.; Kwon, T.K. Molecular mechanisms of curcumin-induced cytotoxicity: Induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis 2003, 24, 1199–1208. [Google Scholar] [PubMed]
  102. Squires, M.S.; Hudson, E.A.; Howells, L.; Sale, S.; Houghton, C.E.; Jones, J.L.; Fox, L.H.; Dickens, M.; Prigent, S.A.; Manson, M.M. Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. Biochem. Pharmacol. 2003, 65, 361–376. [Google Scholar] [PubMed]
  103. Singh, M.; Pandey, A.; Karikari, C.A.; Singh, G.; Rakheja, D. Cell cycle inhibition and apoptosis induced by curcumin in Ewing sarcoma cell line SK-NEP-1. Med. Oncol. 2009, 27, 1096–1101. [Google Scholar] [CrossRef] [PubMed]
  104. Yu, S.; Shen, G.; Khor, T.O.; Kim, J.H.; Kong, A.N. Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. Mol. Cancer Ther. 2008, 7, 2609–2620. [Google Scholar] [PubMed]
  105. Shankar, S.; Chen, Q.; Sarva, K.; Siddiqui, I.; Srivastava, R.K. Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: Molecular mechanisms of apoptosis, migration and angiogenesis. J. Mol. Signal. 2007, 2, 10. [Google Scholar] [PubMed]
  106. Li, M.; Zhang, Z.; Hill, D.L.; Wang, H.; Zhang, R. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res. 2007, 67, 1988–1996. [Google Scholar] [PubMed]
  107. Chaudhary, L.R.; Hruska, K.A. Inhibition of cell survival signal protein kinase B/Akt by curcumin in human prostate cancer cells. J. Cell. Biochem. 2003, 89, 1–5. [Google Scholar] [PubMed]
  108. Beevers, C.S.; Chen, L.; Liu, L.; Luo, Y.; Webster, N.J.; Huang, S. Curcumin disrupts the mammalian target of rapamycin-raptor complex. Cancer Res. 2009, 69, 1000–1008. [Google Scholar] [PubMed]
  109. Chen, L.; Tian, G.; Shao, C.; Cobos, E.; Gao, W. Curcumin modulates eukaryotic initiation factors in human lung adenocarcinoma epithelial cells. Mol. Biol. Rep. 2009, 37, 3105–3110. [Google Scholar] [CrossRef] [PubMed]
  110. Choi, B.H.; Kim, C.G.; Lim, Y.; Shin, S.Y.; Lee, Y.H. Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NF kappa B pathway. Cancer Lett. 2008, 259, 111–118. [Google Scholar] [PubMed]
  111. Kumar, A.P.; Garcia, G.E.; Ghosh, R.; Rajnarayanan, R.V.; Alworth, W.L.; Slaga, T.J. 4-Hydroxy-3-methoxybenzoic acid methyl ester: A curcumin derivative targets Akt/NF kappa B cell survival signaling pathway: Potential for prostate cancer management. Neoplasia 2003, 5, 255–266. [Google Scholar] [PubMed]
  112. Deryugina, E.I.; Quigley, J.P. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006, 25, 9–34. [Google Scholar] [PubMed]
  113. Banerji, A.; Chakrabarti, J.; Mitra, A.; Chatterjee, A. Effect of curcumin on gelatinase A (MMP-2) activity in B16F10 melanoma cells. Cancer Lett. 2004, 211, 235–242. [Google Scholar] [PubMed]
  114. Holy, J. Curcumin inhibits cell motility and alters microfilament organization and function in prostate cancer cells. Cell Motil. Cytoskeleton 2004, 58, 253–268. [Google Scholar] [PubMed]
  115. Hong, J.H.; Ahn, K.S.; Bae, E.; Jeon, S.S.; Choi, H.Y. The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo. Prostate Cancer Prostatic Dis. 2006, 9, 147–152. [Google Scholar] [PubMed]
  116. Lin, S.S.; Lai, K.C.; Hsu, S.C.; Yang, J.S.; Kuo, C.L.; Lin, J.P.; Ma, Y.S.; Wu, C.C.; Chung, J.G. Curcumin inhibits the migration and invasion of human A549 lung cancer cells through the inhibition of matrix metalloproteinase-2 and -9 and Vascular Endothelial Growth Factor (VEGF). Cancer Lett. 2009, 285, 127–133. [Google Scholar] [PubMed]
  117. Aggarwal, B.B.; Shishodia, S.; Takada, Y.; Banerjee, S.; Newman, R.A.; Bueso-Ramos, C.E.; Price, J.E. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin. Cancer Res. 2005, 11, 7490–7498. [Google Scholar] [PubMed]
  118. Liu, Q.; Loo, W.T.; Sze, S.C.; Tong, Y. Curcumin inhibits cell proliferation of MDA-MB-231 and BT-483 breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription. Phytomedicine 2009, 16, 916–922. [Google Scholar] [PubMed]
  119. Voldborg, B.R.; Damstrup, L.; Spang-Thomsen, M.; Poulsen, H.S. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann. Oncol. 1997, 8, 1197–1206. [Google Scholar] [PubMed]
  120. Mitsudomi, T.; Yatabe, Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 2009. [Google Scholar] [CrossRef]
  121. Korutla, L.; Kumar, R. Inhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells. Biochim. Biophys. Acta 1994, 1224, 597–600. [Google Scholar]
  122. Somers-Edgar, T.J.; Taurin, S.; Larsen, L.; Chandramouli, A.; Nelson, M.A.; Rosengren, R.J. Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines. Invest. New Drug. 2009. [Google Scholar] [CrossRef]
  123. Dorai, T.; Gehani, N.; Katz, A. Therapeutic potential of curcumin in human prostate cancer. II. Curcumin inhibits tyrosine kinase activity of epidermal growth factor receptor and depletes the protein. Mol. Urol. 2000, 4, 1–6. [Google Scholar] [PubMed]
  124. Thangapazham, R.L.; Shaheduzzaman, S.; Kim, K.H.; Passi, N.; Tadese, A.; Vahey, M.; Dobi, A.; Srivastava, S.; Maheshwari, R.K. Androgen responsive and refractory prostate cancer cells exhibit distinct curcumin regulated transcriptome. Cancer Biol. Ther. 2008, 7, 1427–1435. [Google Scholar] [PubMed]
  125. Reddy, S.; Rishi, A.K.; Xu, H.; Levi, E.; Sarkar, F.H.; Majumdar, A.P. Mechanisms of curcumin- and EGF-receptor related protein (ERRP)-dependent growth inhibition of colon cancer cells. Nutr. Cancer 2006, 55, 185–194. [Google Scholar] [PubMed]
  126. Korutla, L.; Cheung, J.Y.; Mendelsohn, J.; Kumar, R. Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin. Carcinogenesis 1995, 16, 1741–1745. [Google Scholar] [PubMed]
  127. Chen, A.; Xu, J. Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G447–G456. [Google Scholar] [PubMed]
  128. Kim, J.H.; Xu, C.; Keum, Y.S.; Reddy, B.; Conney, A.; Kong, A.N. Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with beta-phenylethyl isothiocyanate and curcumin. Carcinogenesis 2006, 27, 475–482. [Google Scholar] [PubMed]
  129. Chen, A.; Xu, J.; Johnson, A.C. Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene 2006, 25, 278–287. [Google Scholar] [PubMed]
  130. Arbiser, J.L.; Klauber, N.; Rohan, R.; van Leeuwen, R.; Huang, M.T.; Fisher, C.; Flynn, E.; Byers, H.R. Curcumin is an in vivo inhibitor of angiogenesis. Mol. Med. 1998, 4, 376–383. [Google Scholar] [PubMed]
  131. Gururaj, A.E.; Belakavadi, M.; Venkatesh, D.A.; Marme, D.; Salimath, B.P. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem. Biophys. Res. Commun. 2002, 297, 934–942. [Google Scholar] [PubMed]
  132. Bhandarkar, S.S.; Arbiser, J.L. Curcumin as an inhibitor of angiogenesis. Adv. Exp. Med. Biol. 2007, 595, 185–195. [Google Scholar] [PubMed]
  133. Deng, G.; Yu, J.H.; Ye, Z.Q.; Hu, Z.Q. Curcumin inhibits the expression of vascular endothelial growth factor and androgen-independent prostate cancer cell line PC-3 in vitro. Zhonghua Nan Ke Xue 2008, 14, 116–121. [Google Scholar] [PubMed]
  134. Tharakan, S.T.; Inamoto, T.; Sung, B.; Aggarwal, B.B.; Kamat, A.M. Curcumin potentiates the antitumor effects of gemcitabine in an orthotopic model of human bladder cancer through suppression of proliferative and angiogenic biomarkers. Biochem. Pharmacol. 2010, 79, 218–228. [Google Scholar] [PubMed]
  135. Kumar, A.; Dhawan, S.; Hardegen, N.J.; Aggarwal, B.B. Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem. Pharmacol. 1998, 55, 775–783. [Google Scholar] [PubMed]
  136. Yoysungnoen, P.; Wirachwong, P.; Changtam, C.; Suksamrarn, A.; Patumraj, S. Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice. World J. Gastroenterol. 2008, 14, 2003–2009. [Google Scholar] [PubMed]
  137. Kim, N.W.; Piatyszek, M.A.; Prowse, K.R.; Harley, C.B.; West, M.D.; Ho, P.L.; Coviello, G.M.; Wright, W.E.; Weinrich, S.L.; Shay, J.W. Specific association of human telomerase activity with immortal cells and cancer. Science 1994, 266, 2011–2015. [Google Scholar] [PubMed]
  138. Dikmen, Z.G.; Ozgurtas, T.; Gryaznov, S.M.; Herbert, B.S. Targeting critical steps of cancer metastasis and recurrence using telomerase template antagonists. Biochim. Biophys. Acta 2009, 1792, 240–247. [Google Scholar]
  139. Folini, M.; Gandellini, P.; Zaffaroni, N. Targeting the telosome: Therapeutic implications. Biochim. Biophys. Acta 2009, 1792, 309–316. [Google Scholar]
  140. Kelland, L.R. Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics--current status and future prospects. Eur. J. Cancer 2005, 41, 971–979. [Google Scholar] [PubMed]
  141. Mukherjee Nee Chakraborty, S.; Ghosh, U.; Bhattacharyya, N.P.; Bhattacharya, R.K.; Dey, S.; Roy, M. Curcumin-induced apoptosis in human leukemia cell HL-60 is associated with inhibition of telomerase activity. Mol. Cell. Biochem. 2007, 297, 31–39. [Google Scholar] [PubMed]
  142. Singh, M.; Singh, N. Molecular mechanism of curcumin induced cytotoxicity in human cervical carcinoma cells. Mol. Cell. Biochem. 2009, 325, 107–119. [Google Scholar] [PubMed]
  143. Cui, S.X.; Qu, X.J.; Xie, Y.Y.; Zhou, L.; Nakata, M.; Makuuchi, M.; Tang, W. Curcumin inhibits telomerase activity in human cancer cell lines. Int. J. Mol. Med. 2006, 18, 227–231. [Google Scholar] [PubMed]
  144. Chakraborty, S.; Ghosh, U.; Bhattacharyya, N.P.; Bhattacharya, R.K.; Roy, M. Inhibition of telomerase activity and induction of apoptosis by curcumin in K-562 cells. Mutat. Res. 2006, 596, 81–90. [Google Scholar] [PubMed]
  145. Ramachandran, C.; Fonseca, H.B.; Jhabvala, P.; Escalon, E.A.; Melnick, S.J. Curcumin inhibits telomerase activity through human telomerase reverse transcritpase in MCF-7 breast cancer cell line. Cancer Lett. 2002, 184, 1–6. [Google Scholar] [PubMed]
  146. Lee, J.H.; Chung, I.K. Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT. Cancer Lett. 2009. [Google Scholar] [CrossRef]
  147. Kapoor, N.; Sharma, A.K.; Dwivedi, V.; Kumar, A.; Pati, U.; Misra, K. Telomerase targeted anticancer bioactive prodrug by antisense-based approach. Cancer Lett. 2007, 248, 245–250. [Google Scholar] [PubMed]
  148. Kristensen, L.S.; Nielsen, H.M.; Hansen, L.L. Epigenetics and cancer treatment. Eur. J. Pharmacol. 2009, 625, 131–142. [Google Scholar] [PubMed]
  149. Herman, J.G.; Baylin, S.B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 2003, 349, 2042–2054. [Google Scholar] [PubMed]
  150. Liu, Z.; Xie, Z.; Jones, W.; Pavlovicz, R.E.; Liu, S.; Yu, J.; Li, P.K.; Lin, J.; Fuchs, J.R.; Marcucci, G.; Li, C.; Chan, K.K. Curcumin is a potent DNA hypomethylation agent. Bioorg. Med. Chem. Lett. 2009, 19, 706–709. [Google Scholar] [PubMed]
  151. Ropero, S.; Esteller, M. The role of histone deacetylases (HDACs) in human cancer. Mol. Oncol. 2007, 1, 19–25. [Google Scholar] [PubMed]
  152. Kang, J.; Chen, J.; Shi, Y.; Jia, J.; Zhang, Y. Curcumin-induced histone hypoacetylation: The role of reactive oxygen species. Biochem. Pharmacol. 2005, 69, 1205–1213. [Google Scholar] [PubMed]
  153. Marcu, M.G.; Jung, Y.J.; Lee, S.; Chung, E.J.; Lee, M.J.; Trepel, J.; Neckers, L. Curcumin is an inhibitor of p300 histone acetylatransferase. Med. Chem. 2006, 2, 169–174. [Google Scholar] [PubMed]
  154. Balasubramanyam, K.; Varier, R.A.; Altaf, M.; Swaminathan, V.; Siddappa, N.B.; Ranga, U.; Kundu, T.K. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J. Biol. Chem. 2004, 279, 51163–51171. [Google Scholar] [PubMed]
  155. Koizume, S.; Yokota, N.; Miyagi, E.; Hirahara, F.; Nakamura, Y.; Sakuma, Y.; Yoshida, A.; Kameda, Y.; Tsuchiya, E.; Ruf, W.; Miyagi, Y. Hepatocyte nuclear factor-4-independent synthesis of coagulation factor VII in breast cancer cells and its inhibition by targeting selective histone acetyltransferases. Mol. Cancer Res. 2009, 7, 1928–1936. [Google Scholar] [PubMed]
  156. Bora-Tatar, G.; Dayangac-Erden, D.; Demir, A.S.; Dalkara, S.; Yelekci, K.; Erdem-Yurter, H. Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies. Bioorg. Med. Chem. 2009, 17, 5219–5228. [Google Scholar] [PubMed]
  157. Chen, Y.; Shu, W.; Chen, W.; Wu, Q.; Liu, H.; Cui, G. Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cell. Basic Clin. Pharmacol. Toxicol. 2007, 101, 427–433. [Google Scholar] [PubMed]
  158. Fabbri, M. MicroRNAs and cancer epigenetics. Curr. Opin. Investig. Drugs 2008, 9, 583–590. [Google Scholar] [PubMed]
  159. Valeri, N.; Vannini, I.; Fanini, F.; Calore, F.; Adair, B.; Fabbri, M. Epigenetics, miRNAs, and human cancer: A new chapter in human gene regulation. Mamm. Genome 2009, 20, 573–580. [Google Scholar] [PubMed]
  160. Davalos, V.; Esteller, M. MicroRNAs and cancer epigenetics: A macrorevolution. Curr. Opin. Oncol. 2010, 22, 35–45. [Google Scholar] [PubMed]
  161. Deng, S.; Calin, G.A.; Croce, C.M.; Coukos, G.; Zhang, L. Mechanisms of microRNA deregulation in human cancer. Cell Cycle 2008, 7, 2643–2646. [Google Scholar] [PubMed]
  162. Zhang, H.; Li, Y.; Lai, M. The microRNA network and tumor metastasis. Oncogene 2009. [Google Scholar] [CrossRef]
  163. Davis, C.D.; Ross, S.A. Evidence for dietary regulation of microRNA expression in cancer cells. Nutr. Rev. 2008, 66, 477–482. [Google Scholar] [PubMed]
  164. Sun, M.; Estrov, Z.; Ji, Y.; Coombes, K.R.; Harris, D.H.; Kurzrock, R. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol. Cancer Ther. 2008, 7, 464–473. [Google Scholar] [PubMed]
  165. Yang, J.; Cao, Y.; Sun, J.; Zhang, Y. Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells. Med. Oncol. 2009. [Google Scholar] [CrossRef]
  166. Reuter, S.; Eifes, S.; Dicato, M.; Aggarwal, B.B.; Diederich, M. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem. Pharmacol. 2008, 76, 1340–1351. [Google Scholar] [PubMed]
  167. de Bruin, E.C.; Medema, J.P. Apoptosis and non-apoptotic deaths in cancer development and treatment response. Cancer Treat. Rev. 2008, 34, 737–749. [Google Scholar] [PubMed]
  168. Karmakar, S.; Banik, N.L.; Patel, S.J.; Ray, S.K. Curcumin activated both receptor-mediated and mitochondria-mediated proteolytic pathways for apoptosis in human glioblastoma T98G cells. Neurosci. Lett. 2006, 407, 53–58. [Google Scholar] [PubMed]
  169. Cao, J.; Liu, Y.; Jia, L.; Zhou, H.M.; Kong, Y.; Yang, G.; Jiang, L.P.; Li, Q.J.; Zhong, L.F. Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma G2 cells. Free Radic. Biol. Med. 2007, 43, 968–975. [Google Scholar] [PubMed]
  170. Song, G.; Mao, Y.B.; Cai, Q.F.; Yao, L.M.; Ouyang, G.L.; Bao, S.D. Curcumin induces human HT-29 colon adenocarcinoma cell apoptosis by activating p53 and regulating apoptosis-related protein expression. Braz. J. Med. Biol. Res. 2005, 38, 1791–1798. [Google Scholar] [PubMed]
  171. Tian, B.; Wang, Z.; Zhao, Y.; Wang, D.; Li, Y.; Ma, L.; Li, X.; Li, J.; Xiao, N.; Tian, J.; Rodriguez, R. Effects of curcumin on bladder cancer cells and development of urothelial tumors in a rat bladder carcinogenesis model. Cancer Lett. 2008, 264, 299–308. [Google Scholar] [PubMed]
  172. Ghosh, A.K.; Kay, N.E.; Secreto, C.R.; Shanafelt, T.D. Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin. Cancer Res. 2009, 15, 1250–1258. [Google Scholar] [PubMed]
  173. Anto, R.J.; Mukhopadhyay, A.; Denning, K.; Aggarwal, B.B. Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: Its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 2002, 23, 143–150. [Google Scholar] [PubMed]
  174. Bush, J.A.; Cheung, K.J., Jr.; Li, G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp. Cell. Res. 2001, 271, 305–314. [Google Scholar] [PubMed]
  175. Moragoda, L.; Jaszewski, R.; Majumdar, A.P. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res. 2001, 21, 873–878. [Google Scholar] [PubMed]
  176. Friedman, L.; Lin, L.; Ball, S.; Bekaii-Saab, T.; Fuchs, J.; Li, P.K.; Li, C.; Lin, J. Curcumin analogues exhibit enhanced growth suppressive activity in human pancreatic cancer cells. Anticancer Drug. 2009, 20, 444–449. [Google Scholar]
  177. Karunagaran, D.; Rashmi, R.; Kumar, T.R. Induction of apoptosis by curcumin and its implications for cancer therapy. Curr. Cancer Drug Targets 2005, 5, 117–129. [Google Scholar] [PubMed]
  178. Castedo, M.; Perfettini, J.L.; Roumier, T.; Valent, A.; Raslova, H.; Yakushijin, K.; Horne, D.; Feunteun, J.; Lenoir, G.; Medema, R.; Vainchenker, W.; Kroemer, G. Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy. Oncogene 2004, 23, 4362–4370. [Google Scholar] [PubMed]
  179. Castedo, M.; Perfettini, J.L.; Roumier, T.; Andreau, K.; Medema, R.; Kroemer, G. Cell death by mitotic catastrophe: A molecular definition. Oncogene 2004, 23, 2825–2837. [Google Scholar] [PubMed]
  180. Roninson, I.B.; Broude, E.V.; Chang, B.D. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist. Update. 2001, 4, 303–313. [Google Scholar]
  181. Holy, J.M. Curcumin disrupts mitotic spindle structure and induces micronucleation in MCF-7 breast cancer cells. Mutat. Res. 2002, 518, 71–84. [Google Scholar] [PubMed]
  182. Magalska, A.; Sliwinska, M.; Szczepanowska, J.; Salvioli, S.; Franceschi, C.; Sikora, E. Resistance to apoptosis of HCW-2 cells can be overcome by curcumin- or vincristine-induced mitotic catastrophe. Int. J. Cancer 2006, 119, 1811–1818. [Google Scholar] [PubMed]
  183. Wolanin, K.; Magalska, A.; Mosieniak, G.; Klinger, R.; McKenna, S.; Vejda, S.; Sikora, E.; Piwocka, K. Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis-resistant Bcr-Abl-expressing cells. Mol. Cancer Res. 2006, 4, 457–469. [Google Scholar] [PubMed]
  184. O'Sullivan-Coyne, G.; O'Sullivan, G.C.; O'Donovan, T.R.; Piwocka, K.; McKenna, S.L. Curcumin induces apoptosis-independent death in oesophageal cancer cells. Br. J. Cancer 2009, 101, 1585–1595. [Google Scholar] [PubMed]
  185. Dempe, J.S.; Pfeiffer, E.; Grimm, A.S.; Metzler, M. Metabolism of curcumin and induction of mitotic catastrophe in human cancer cells. Mol. Nutr. Food Res. 2008, 52, 1074–1081. [Google Scholar] [PubMed]
  186. Basile, V.; Ferrari, E.; Lazzari, S.; Belluti, S.; Pignedoli, F.; Imbriano, C. Curcumin derivatives: Molecular basis of their anti-cancer activity. Biochem. Pharmacol. 2009, 78, 1305–1315. [Google Scholar] [PubMed]
  187. Chen, N.; Karantza-Wadsworth, V. Role and regulation of autophagy in cancer. Biochim. Biophys. Acta 2009, 1793, 1516–1523. [Google Scholar]
  188. Kondo, Y.; Kanzawa, T.; Sawaya, R.; Kondo, S. The role of autophagy in cancer development and response to therapy. Nat. Rev. Cancer 2005, 5, 726–734. [Google Scholar] [PubMed]
  189. Morselli, E.; Galluzzi, L.; Kepp, O.; Vicencio, J.M.; Criollo, A.; Maiuri, M.C.; Kroemer, G. Anti- and pro-tumor functions of autophagy. Biochim. Biophys. Acta 2009, 1793, 1524–1532. [Google Scholar]
  190. Aoki, H.; Takada, Y.; Kondo, S.; Sawaya, R.; Aggarwal, B.B.; Kondo, Y. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: Role of Akt and extracellular signal-regulated kinase signaling pathways. Mol. Pharmacol. 2007, 72, 29–39. [Google Scholar] [PubMed]
  191. Shinojima, N.; Yokoyama, T.; Kondo, Y.; Kondo, S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 2007, 3, 635–637. [Google Scholar] [PubMed]
  192. Verma, S.P.; Salamone, E.; Goldin, B. Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides. Biochem. Biophys. Res. Commun. 1997, 233, 692–696. [Google Scholar] [PubMed]
  193. Liu, Y.; Chang, R.L.; Cui, X.X.; Newmark, H.L.; Conney, A.H. Synergistic effects of curcumin on all-trans retinoic acid- and 1 alpha,25-dihydroxyvitamin D3-induced differentiation in human promyelocytic leukemia HL-60 cells. Oncol. Res. 1997, 9, 19–29. [Google Scholar] [PubMed]
  194. Mosieniak, G.; Sliwinska, M.; Piwocka, K.; Sikora, E. Curcumin abolishes apoptosis resistance of calcitriol-differentiated HL-60 cells. FEBS Lett. 2006, 580, 4653–4660. [Google Scholar] [PubMed]
  195. Sreepriya, M.; Bali, G. Effects of administration of embelin and curcumin on lipid peroxidation, hepatic glutathione antioxidant defense and hematopoietic system during N-nitrosodiethylamine/Phenobarbital-induced hepatocarcinogenesis in Wistar rats. Mol. Cell. Biochem. 2006, 284, 49–55. [Google Scholar] [PubMed]
  196. Khor, T.O.; Keum, Y.S.; Lin, W.; Kim, J.H.; Hu, R.; Shen, G.; Xu, C.; Gopalakrishnan, A.; Reddy, B.; Zheng, X.; Conney, A.H.; Kong, A.N. Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res. 2006, 66, 613–621. [Google Scholar] [PubMed]
  197. Majumdar, A.P.; Banerjee, S.; Nautiyal, J.; Patel, B.B.; Patel, V.; Du, J.; Yu, Y.; Elliott, A.A.; Levi, E.; Sarkar, F.H. Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr. Cancer 2009, 61, 544–553. [Google Scholar] [PubMed]
  198. Khafif, A.; Schantz, S.P.; Chou, T.C.; Edelstein, D.; Sacks, P.G. Quantitation of chemopreventive synergism between (-)-epigallocatechin-3-gallate and curcumin in normal, premalignant and malignant human oral epithelial cells. Carcinogenesis 1998, 19, 419–424. [Google Scholar] [PubMed]
  199. Cruz-Correa, M.; Shoskes, D.A.; Sanchez, P.; Zhao, R.; Hylind, L.M.; Wexner, S.D.; Giardiello, F.M. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2006, 4, 1035–1038. [Google Scholar] [PubMed]
  200. Chendil, D.; Ranga, R.S.; Meigooni, D.; Sathishkumar, S.; Ahmed, M.M. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene 2004, 23, 1599–1607. [Google Scholar] [PubMed]
  201. Javvadi, P.; Segan, A.T.; Tuttle, S.W.; Koumenis, C. The chemopreventive agent curcumin is a potent radiosensitizer of human cervical tumor cells via increased reactive oxygen species production and overactivation of the mitogen-activated protein kinase pathway. Mol. Pharmacol. 2008, 73, 1491–1501. [Google Scholar] [PubMed]
  202. Bava, S.V.; Puliappadamba, V.T.; Deepti, A.; Nair, A.; Karunagaran, D.; Anto, R.J. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J. Biol. Chem. 2005, 280, 6301–6308. [Google Scholar] [PubMed]
  203. Kang, H.J.; Lee, S.H.; Price, J.E.; Kim, L.S. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model. Breast J. 2009, 15, 223–229. [Google Scholar] [PubMed]
  204. Sen, S.; Sharma, H.; Singh, N. Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. Biochem. Biophys. Res. Commun. 2005, 331, 1245–1252. [Google Scholar] [PubMed]
  205. Lev-Ari, S.; Strier, L.; Kazanov, D.; Madar-Shapiro, L.; Dvory-Sobol, H.; Pinchuk, I.; Marian, B.; Lichtenberg, D.; Arber, N. Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells. Clin. Cancer Res. 2005, 11, 6738–6744. [Google Scholar] [PubMed]
  206. Lev-Ari, S.; Zinger, H.; Kazanov, D.; Yona, D.; Ben-Yosef, R.; Starr, A.; Figer, A.; Arber, N. Curcumin synergistically potentiates the growth inhibitory and pro-apoptotic effects of celecoxib in pancreatic adenocarcinoma cells. Biomed. Pharmacother. 2005, 59, S276–S280. [Google Scholar] [PubMed]
  207. Du, B.; Jiang, L.; Xia, Q.; Zhong, L. Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29. Chemotherapy 2006, 52, 23–28. [Google Scholar] [PubMed]
  208. Koo, J.Y.; Kim, H.J.; Jung, K.O.; Park, K.Y. Curcumin inhibits the growth of AGS human gastric carcinoma cells in vitro and shows synergism with 5-fluorouracil. J. Med. Food 2004, 7, 117–121. [Google Scholar] [PubMed]
  209. Patel, B.B.; Sengupta, R.; Qazi, S.; Vachhani, H.; Yu, Y.; Rishi, A.K.; Majumdar, A.P. Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF-1R. Int. J. Cancer 2008, 122, 267–273. [Google Scholar] [PubMed]
  210. Howells, L.M.; Mitra, A.; Manson, M.M. Comparison of oxaliplatin- and curcumin-mediated antiproliferative effects in colorectal cell lines. Int. J. Cancer 2007, 121, 175–183. [Google Scholar] [PubMed]
  211. Siddik, Z.H. Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene 2003, 22, 7265–7279. [Google Scholar] [PubMed]
  212. Heffeter, P.; Jungwirth, U.; Jakupec, M.; Hartinger, C.; Galanski, M.; Elbling, L.; Micksche, M.; Keppler, B.; Berger, W. Resistance against novel anticancer metal compounds: Differences and similarities. Drug Resist. Update. 2008, 11, 1–16. [Google Scholar]
  213. Weir, N.M.; Selvendiran, K.; Kutala, V.K.; Tong, L.; Vishwanath, S.; Rajaram, M.; Tridandapani, S.; Anant, S.; Kuppusamy, P. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol. Ther. 2007, 6, 178–184. [Google Scholar] [PubMed]
  214. Montopoli, M.; Ragazzi, E.; Froldi, G.; Caparrotta, L. Cell-cycle inhibition and apoptosis induced by curcumin and cisplatin or oxaliplatin in human ovarian carcinoma cells. Cell Prolifration 2009, 42, 195–206. [Google Scholar]
  215. Chanvorachote, P.; Pongrakhananon, V.; Wannachaiyasit, S.; Luanpitpong, S.; Rojanasakul, Y.; Nimmannit, U. Curcumin sensitizes lung cancer cells to cisplatin-induced apoptosis through superoxide anion-mediated Bcl-2 degradation. Cancer Invest. 2009, 27, 624–635. [Google Scholar] [PubMed]
  216. Chan, M.M.; Fong, D.; Soprano, K. J.; Holmes, W.F.; Heverling, H. Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents. J. Cell. Physiol. 2003, 194, 63–70. [Google Scholar] [PubMed]
  217. Yu, Y.; Kanwar, S.S.; Patel, B.B.; Nautiyal, J.; Sarkar, F.H.; Majumdar, A.P. Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Transl. Oncol. 2009, 2, 321–328. [Google Scholar] [PubMed]
  218. Sung, B.; Kunnumakkara, A.B.; Sethi, G.; Anand, P.; Guha, S.; Aggarwal, B.B. Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model. Mol. Cancer Ther. 2009, 8, 959–970. [Google Scholar] [PubMed]
  219. Venkatesan, N. Curcumin attenuation of acute adriamycin myocardial toxicity in rats. Br. J. Pharmacol. 1998, 124, 425–427. [Google Scholar] [PubMed]
  220. Bayet-Robert, M.; Kwiatkowski, F.; Leheurteur, M.; Gachon, F.; Planchat, E.; Abrial, C.; Mouret-Reynier, M.A.; Durando, X.; Barthomeuf, C.; Chollet, P. Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol. Ther. 2010, 9. [Google Scholar]
  221. Deeb, D.; Jiang, H.; Gao, X.; Hafner, M.S.; Wong, H.; Divine, G.; Chapman, R.A.; Dulchavsky, S.A.; Gautam, S.C. Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-kappaB through suppression of IkappaBalpha phosphorylation. Mol. Cancer Ther. 2004, 3, 803–812. [Google Scholar] [PubMed]
  222. Deeb, D.; Xu, Y.X.; Jiang, H.; Gao, X.; Janakiraman, N.; Chapman, R.A.; Gautam, S.C. Curcumin (diferuloyl-methane) enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in LNCaP prostate cancer cells. Mol. Cancer Ther. 2003, 2, 95–103. [Google Scholar] [PubMed]
  223. Deeb, D.D.; Jiang, H.; Gao, X.; Divine, G.; Dulchavsky, S.A.; Gautam, S.C. Chemosensitization of hormone-refractory prostate cancer cells by curcumin to TRAIL-induced apoptosis. J. Exp. Ther. Oncol. 2005, 5, 81–91. [Google Scholar] [PubMed]
  224. Andrzejewski, T.; Deeb, D.; Gao, X.; Danyluk, A.; Arbab, A.S.; Dulchavsky, S.A.; Gautam, S.C. Therapeutic efficacy of curcumin/TRAIL combination regimen for hormone-refractory prostate cancer. Oncol. Res. 2008, 17, 257–267. [Google Scholar] [PubMed]
  225. Shankar, S.; Ganapathy, S.; Chen, Q.; Srivastava, R.K. Curcumin sensitizes TRAIL-resistant xenografts: Molecular mechanisms of apoptosis, metastasis and angiogenesis. Mol. Cancer 2008, 7, 16. [Google Scholar] [PubMed]
  226. Mancuso, C.; Barone, E. Curcumin in clinical practice: Myth or reality? Trends Pharmacol. Sci. 2009, 30, 333–334. [Google Scholar]
  227. National Toxicology Program. NTP Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (CAS No. 8024-37-1) (Major Component 79%-85% Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl. Toxicol. Program Tech. Rep. Ser. 1993, 427, 1–275. [Google Scholar] [PubMed]
  228. Dance-Barnes, S.T.; Kock, N.D.; Moore, J.E.; Lin, E.Y.; Mosley, L.J.; D'Agostino, R.B., Jr.; McCoy, T.P.; Townsend, A.J.; Miller, M.S. Lung tumor promotion by curcumin. Carcinogenesis 2009, 30, 1016–1023. [Google Scholar] [PubMed]
  229. Moos, P.J.; Edes, K.; Mullally, J.E.; Fitzpatrick, F.A. Curcumin impairs tumor suppressor p53 function in colon cancer cells. Carcinogenesis 2004, 25, 1611–1617. [Google Scholar] [PubMed]
  230. Lopez-Lazaro, M. Anticancer and carcinogenic properties of curcumin: Considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent. Mol. Nutr. Food Res. 2008, 52, S103–S127. [Google Scholar] [PubMed]
  231. Jiao, Y.; Wilkinson, J.T.; Di, X.; Wang, W.; Hatcher, H.; Kock, N.D.; D'Agostino, R., Jr.; Knovich, M.A.; Torti, F.M.; Torti, S.V. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelat. Blood 2009, 113, 462–469. [Google Scholar] [PubMed]
  232. Giri, A.K.; Das, S.K.; Talukder, G.; Sharma, A. Sister chromatid exchange and chromosome aberrations induced by curcumin and tartrazine on mammalian cells in vivo. Cytobios 1990, 62, 111–117. [Google Scholar] [PubMed]
  233. Cao, J.; Jia, L.; Zhou, H.M.; Liu, Y.; Zhong, L.F. Mitochondrial and nuclear DNA damage induced by curcumin in human hepatoma G2 cells. Toxicol. Sci. 2006, 91, 476–483. [Google Scholar] [PubMed]
  234. Somasundaram, S.; Edmund, N.A.; Moore, D.T.; Small, G.W.; Shi, Y.Y.; Orlowski, R.Z. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res. 2002, 62, 3868–3875. [Google Scholar] [PubMed]
Back to TopTop