The Role of Resveratrol in Cancer Management: From Monotherapy to Combination Regimens

Abstract

Resveratrol, a naturally occurring polyphenol found in grapes, berries, and peanuts, has garnered significant attention for its potential anti-cancer properties. This review provides a comprehensive analysis of its role in cancer therapy, both as a standalone treatment and in combination with other therapeutic approaches. This review explores the molecular mechanisms underlying resveratrol’s anti-cancer effects, including its antioxidant activity, modulation of cellular signaling pathways, antiproliferative properties, anti-inflammatory effects, and epigenetic influences. This review also examines in vitro and in vivo studies that highlight resveratrol’s efficacy against various cancer types. Furthermore, the synergistic effects of resveratrol when used in conjunction with conventional treatments like chemotherapy and radiotherapy, as well as targeted therapies and immunotherapies, are discussed. Despite promising preclinical results, this review addresses the challenges and limitations faced in translating these findings into clinical practice, including issues of bioavailability and toxicity. Finally, it outlines future research directions and the potential for resveratrol to enhance existing cancer treatment regimens. This review aims to provide a thorough understanding of resveratrol’s therapeutic potential and to identify areas for further investigation in the quest for effective cancer treatments.

1. Introduction

Cancer encompasses a diverse group of diseases marked by uncontrolled cellular growth and the potential to invade other parts of the body, leading to severe health consequences and high mortality rates [1]. With over 100 different types, including breast, skin, lung, colon, and prostate cancer and lymphoma, this disease affects millions of people worldwide, posing one of the most significant challenges in modern medicine [2]. The complexity of cancer, coupled with the limitations of conventional treatments such as surgery, radiation, and chemotherapy, underscores the urgent need for the development of novel therapies [3,4]. These traditional treatments often cause significant side effects and may not be suitable for all cancer types or patients [5]. Additionally, treatment resistance and tumor heterogeneity further complicate disease management [6,7].

Given these challenges, the search for novel therapeutic agents has become imperative. One such promising agent is resveratrol, a naturally occurring polyphenolic compound found in various plants, including grapes and berries [8]. Resveratrol gained widespread attention due to its presence in red wine and its potential health benefits, particularly its connection to the ‘French Paradox’, a phenomenon where the French exhibit a low incidence of heart disease despite a diet rich in saturated fats [9,10]. Chemically, resveratrol, known as 3,5,4’-trihydroxystilbene, is classified as a stilbenoid, characterized by two phenol rings connected by a styrene double bond (Figure 1) [11].

Biologically, resveratrol exhibits a range of properties that contribute to its therapeutic potential, including antioxidant [12], anti-inflammatory [13], and anti-carcinogenic effects [14]. Due to its ability to modulate various molecular pathways, resveratrol is a promising candidate for preventing and treating a range of diseases, such as cardiovascular diseases [15], cancer [16], and neurodegenerative disorders [17,18]. Ongoing research continues to uncover the mechanisms behind resveratrol’s actions, making its potential applications in medicine and health promotion an exciting and active area of scientific investigation.

This review seeks to provide a comprehensive analysis of resveratrol’s mechanisms of action, its potential as a monotherapy in cancer treatment, and its synergistic effects when combined with other cancer therapies.

2. Mechanisms of Action of Resveratrol

2.1. Antioxidant Activity

Resveratrol is well known for its potent antioxidant activity, which is one of its most extensively studied biological properties, particularly in the context of cancer. As an antioxidant, it functions by neutralizing harmful free radicals (e.g., reactive oxygen species (ROS) and reactive nitrogen species (RNS))—unstable molecules that can cause cellular damage through oxidative stress [19]. Oxidative stress significantly contributes to cancer initiation and progression by damaging essential cellular components such as DNA, proteins, and lipids, thus facilitating tumor development [20,21,22]. In addition to scavenging ROS and RNS to prevent oxidative damage, resveratrol also chelates metal ions, such as iron and copper, which are known to catalyze the production of free radicals, reducing their availability for oxidative reactions [23,24]. Resveratrol also activates various signaling pathways that upregulate the expression of endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase, all of which play crucial roles in the detoxification of ROS [12]. Furthermore, resveratrol inhibits pro-oxidant enzymes such as NADPH oxidase and xanthine oxidase, which are responsible for producing ROS, thereby decreasing the overall oxidative stress burden in the tumor microenvironment [25]. Moreover, since oxidative stress is a significant factor in cancer initiation and progression, resveratrol’s ability to mitigate oxidative damage and modulate cell signaling pathways involved in cell growth and apoptosis makes it a promising candidate for cancer prevention and therapy [26].

Additionally, resveratrol’s antioxidant properties have broader implications for other diseases related to oxidative stress. In cardiovascular diseases, for instance, resveratrol helps to prevent the oxidation of low-density lipoprotein (LDL) cholesterol [15], a key step in the development of atherosclerosis, contributing to its cardioprotective effects [27]. Similarly, its ability to protect neurons from oxidative damage shows promise in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease [28].

In addition to its potent antioxidant properties, resveratrol also exerts significant effects through the modulation of cellular signaling pathways.

2.2. Modulation of Cellular Signaling

Resveratrol’s modulation of various cellular signaling pathways underpins its broad spectrum of biological activities. This modulation is crucial to its therapeutic potential, especially in cancer prevention and treatment. Resveratrol influences multiple signaling cascades that regulate cell proliferation, apoptosis, inflammation, and oxidative stress, thereby affecting key pathways involved in cancer cell growth, survival, and metastasis.

NAD-Dependent Deacetylase Sirtuin-1 (SIRT1)

One of the primary mechanisms through which resveratrol exerts its effects is by activating the sirtuin family of proteins, particularly SIRT1 [29]. SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that plays a crucial role in regulating cellular metabolism, aging, and inflammation [30,31,32]. The activation of SIRT1 by resveratrol results in the deacetylation and activation of various transcription factors and co-regulators, leading to a wide range of beneficial cellular effects. When SIRT1 is activated by resveratrol, it deacetylates the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [33]. Deacetylation of PGC-1α enhances its activity, leading to an increase in the number and function of mitochondria [34], which are essential for energy production in cells. This upregulation of mitochondrial function enhances cellular energy metabolism and increases resistance to oxidative stress [35].

In addition to PGC-1α, SIRT1 activation also influences other important transcription factors and proteins. For instance, SIRT1 deacetylates and modulates the activity of the tumor suppressor protein p53 [36,37], which is involved in cell cycle regulation [38] and apoptosis [39]. Through the regulation of p53, resveratrol promotes cell survival under stress conditions while inducing apoptosis in damaged or tumor cells. Additionally, SIRT1 activation by resveratrol can inhibit the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway [40]. NF-κB is a transcription factor that regulates genes involved in inflammation, immune response, and cell survival [41]. By inhibiting NF-κB, SIRT1 reduces inflammation and may help prevent chronic inflammatory diseases and cancer progression.

Resveratrol also significantly affects the PI3K/Akt signaling pathway, a crucial regulator of cell growth, survival, and metabolism [42]. By inhibiting PI3K activity, resveratrol reduces the phosphorylation and activation of Akt, leading to decreased cell proliferation and enhanced apoptosis [43]. This modulation of the PI3K/Akt pathway not only hampers tumor growth and promotes cancer cell death but also contributes to resveratrol’s anti-inflammatory and metabolic regulatory effects.

2.3. Antiproliferative Effects

By inhibiting the cell cycle and inducing apoptosis, resveratrol exerts significant antiproliferative effects on cancer cells. Research shows that it induces cell cycle arrest at various stages, particularly the G1 and G2/M phases [44,45,46]. This arrest is achieved through the modulation of cyclins and cyclin-dependent kinases (CDKs), which are essential for the progression of the cell cycle [47]. By altering the expression and activity of these proteins, resveratrol halts the uncontrolled growth of cancer cells. In addition, it promotes apoptosis (programmed cell death) in cancer cells [48,49]. It activates intrinsic apoptotic pathways by upregulating pro-apoptotic factors like Bax and downregulating anti-apoptotic proteins such as Bcl-2 [50]. This shift in the balance between pro- and anti-apoptotic signals leads to mitochondrial dysfunction and the release of cytochrome c, which activates caspases and triggers cell death [51].

2.4. Anti-Inflammatory Effects

Resveratrol exerts significant anti-inflammatory effects through several key mechanisms, which contribute to its therapeutic potential in treating chronic inflammatory conditions and related diseases. Resveratrol modulates inflammation by inhibiting the NF-κB signaling pathway. NF-κB is a crucial transcription factor that regulates the expression of various pro-inflammatory cytokines, adhesion molecules, and enzymes involved in inflammation [41]. By inhibiting NF-κB activation, it effectively reduces the production of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2), thereby mitigating the inflammatory response [52]. In addition, resveratrol directly inhibits COX-2 activity, which is critical for the synthesis of prostaglandins involved in mediating inflammation and pain [53]. Since chronic inflammation is a well-established risk factor for cancer, its anti-inflammatory effects may significantly contribute to its anticancer properties.

2.5. Epigenetic Modulation

Resveratrol significantly influences gene expression through epigenetic modulation, a process that alters gene expression without changing the DNA sequence [54]. This capability is central to its therapeutic potential across various diseases, including cancer. One of the main ways it affects epigenetic regulation is by modifying histone acetylation. Resveratrol acts as a potent activator of sirtuins, particularly SIRT1. SIRT1 deacetylates histones, leading to changes in chromatin structure and, consequently, altering gene expression [55].

Resveratrol also influences DNA methylation patterns, another crucial aspect of epigenetic control. DNA methylation involves adding methyl groups to cytosine residues within CG dinucleotides, typically leading to gene silencing [56]. Resveratrol can affect the activity of DNA methyltransferases, the enzymes responsible for DNA methylation, thereby modifying the expression of genes involved in cell growth, apoptosis and inflammation [57].

Additionally, it impacts the expression of microRNAs (miRNAs), which are small non-coding RNAs that regulate gene expression after transcription [58,59]. By altering miRNA expression, it can affect numerous cellular processes, including cell cycle regulation, apoptosis and responses to cellular stress. These changes can lead to the suppression of oncogenes and the activation of tumor suppressor genes, further enhancing resveratrol’s potential as an anti-cancer agent [60].

The following table (

Table 1. Summary of the anticancer mechanisms of resveratrol.

Mechanism	Description	Implications for Cancer
Antioxidant Activity	Scavenges ROS and RNS Chelates iron and copper	Reduces oxidative stress Prevents DNA, protein, and lipid damage
Modulation of Cellular Signaling	Regulates cell proliferation, apoptosis, inflammation Affects oxidative stress regulation	Inhibits cancer growth and metastasis
SIRT1 Activation	Activates SIRT1 deacetylase Deacetylates PGC-1α and p53	Enhances mitochondrial function Regulates apoptosis and reduces inflammation
PI3K/Akt Inhibition	Inhibits PI3K/Akt pathway Reduces phosphorylation of Akt	Decreases cell proliferation Promotes apoptosis
Antiproliferative Effects	Induces cell cycle arrest (G1, G2/M phases) Modulates cyclins and CDKs	Halts cancer cell growth Promotes programmed cell death
Anti-inflammatory Effects	Inhibits NF-κB pathway Reduces pro-inflammatory cytokines (TNF-α, IL-6)	Mitigates chronic inflammation Reduces cancer-promoting inflammation
Epigenetic Modulation	- Affects histone acetylation - Alters DNA methylation and microRNA expression	- Regulates oncogene and tumor suppressor gene expression - Enhances anticancer potential

) summarizes the key mechanisms through which resveratrol exerts its anticancer effects. This overview highlights the primary biological activities of resveratrol, detailing the associated pathways, descriptions of their functions, and implications for cancer prevention and therapy.

3. Application of Resveratrol in Cancer Treatment

3.1. In Vitro Studies

In vitro studies have provided substantial insights into the application of resveratrol in cancer treatment, demonstrating its potential as an effective anti-cancer agent. These studies have shown that it exerts multiple anti-cancer effects on various cancer cell lines, including those of breast, prostate, colon, lung, and liver cancers.

3.1.1. Lung Cancer

In studies focusing on non-small lung cancer (NSCLC) cell lines such as A549 and H460, resveratrol has demonstrated potential as a treatment option. Resveratrol treatment suppressed cell growth in these NSCLC cell lines, indicating its ability to inhibit proliferation. Additionally, it increased the expression of microtubule-associated protein 1 light chain 3 (LC3), which plays a crucial role in autophagy—a cellular process that degrades and recycles damaged or unnecessary cellular components [61]. The treatment of A549 cells with resveratrol has been found to induce apoptosis and cause G1 cell cycle arrest, halting cell cycle progression at the G1 phase. This effect is accompanied by the upregulation of p53 and p21 [62]. Ebi et al. [63] studied resveratrol’s effects on three human NSCLC cell lines: A427, NCI-H23, and A549. The treatment of these cancer cells resulted in the inhibition of the PI3K pathway, a critical signaling pathway regulating cell proliferation, growth, survival, metabolism, and protein synthesis. Additionally, treatment with resveratrol decreased mTOR phosphorylation, indicating reduced mTOR activity. Since mTOR is vital for regulating cell growth and protein synthesis, its inhibition by resveratrol can hinder cancer cell proliferation and survival [64]. In H460 cells, resveratrol decreased cell viability and proliferation while inducing significant apoptosis. This apoptosis was associated with increased hydrogen peroxide (H₂O₂) production, the activation of Bid, PARP, and caspase 8, and the downregulation of pEGFR, pAkt, c-FLIP, and NFkB protein expression [65]. Li et al. [66] used the small cell lung cancer (SCLC) cell line H446 to investigate the antitumor mechanism of resveratrol. Their results showed that resveratrol inhibited H446 cell viability, induced apoptosis, increased cytochrome c expression, inhibited the PI3K/Akt/c-Myc pathway, and promoted AIF translocation from the cytoplasm to the nucleus. This study therefore suggests that in SCLC H446 cells, resveratrol may reduce cell viability and induce apoptosis by affecting the PI3K/Akt/c-Myc pathway, with oxidative stress and mitochondrial membrane depolarization contributing to these effects.

3.1.2. Prostate Cancer

Resveratrol exhibits varying effects on growth, cell cycle arrest, and apoptosis induction in human prostate cancer cell lines such as PC-3 and C42B [67,68]. Substantial evidence indicates that its anti-prostate cancer effects are primarily mediated through its targeting of the androgen receptor (AR) and its regulated genes [69,70,71]. A study conducted by Farhan demonstrated that resveratrol reduces cell growth and induces apoptosis-like cell death in the PC-3 and C42B cell lines. These effects were significantly inhibited by copper chelators and ROS. This suggests that intracellular copper reacts with resveratrol to generate ROS, resulting in DNA damage [24].

3.1.3. Breast Cancer

Resveratrol has been shown to inhibit the proliferation of MCF-7 breast cancer cells in a dose- and time-dependent manner. Significant cytotoxic effects were observed even at a concentration of 100 μM after 24 h of treatment. Compared to untreated cells, it reduced the viability of MCF-7 cells to approximately 57.5%, yielding a half-maximal inhibitory concentration (IC₅₀) of 51.18 μM. Additionally, treatment with resveratrol led to the induction of apoptosis in this cell line, as indicated by elevated levels of apoptosis markers [72]. In another study, resveratrol moderately inhibited MCF-7 cell viability. Specifically, it increased the number of early apoptotic cells in MCF-7 [49]. Kim et al. [73] demonstrated that resveratrol reduces the expression of YAP target genes and inhibits breast cancer cell invasion. Resveratrol accomplishes this by activating Lats1, resulting in the inactivation of YAP. Notably, it also inactivates RhoA, which enhances Lats1 activation and promotes YAP phosphorylation.

3.1.4. Colorectal Cancer

Resveratrol reduces the proliferation and invasion of colorectal cancer (CRC) cells by activating SIRT1, decreasing the NF-κB-mediated inflammatory pathway, and inhibiting the focal adhesion kinase (FAK) activity. This results in a reduction in focal adhesion molecules and an increase in apoptosis. Furthermore, it inhibits the invasion, colony formation, and cell growth of CRC cells, as well as the expression of β1-Integrin and the activation of FAK in an alginate cancer microenvironment [74]. It has also been shown to suppress the Wnt signaling pathway, which is crucial in the development of several serious diseases, including cancer [75]. Resveratrol reduces this pathway in a dose-dependent manner, reducing the expression of key target genes such as cyclin D1 and c-Myc, thereby inhibiting the growth of Wnt-induced and Wnt-driven colorectal cancer (CRC) cells [76]. Additionally, it inhibits the activity of several enzymes involved in DNA replication and cell proliferation [77]. These combined effects likely contribute to its ability to modulate cell proliferation.

3.1.5. Liver Cancer

Resveratrol has been shown to inhibit the proliferation of HepG2 hepatocellular carcinoma cells in a dose- and time-dependent manner. Significant cytotoxic effects were observed even at a concentration of 100 μM after 24 h of treatment. Compared to untreated cells, resveratrol reduced the viability of HepG2 cells by about 56.2%, with an IC₅₀ of 57.4 μM [72]. Dai et al. [78] found that it induces apoptosis and inhibits the proliferation, migration, and invasion of the HepG2 and Hep3B hepatocellular carcinoma cell lines. Resveratrol reduced the expression of MARCH1 and phospho-protein kinase B (p-AKT), while increasing the expression of the tumor suppressor PTEN in a dose-dependent manner. Another study demonstrated that it significantly impedes the respiratory metabolism of hepatocellular carcinoma cells, thereby inhibiting their proliferation, migration and invasion, while also promoting apoptosis [79]. Resveratrol inhibited both anchorage-dependent and anchorage-independent growth of hepatocellular carcinoma cells in a dose-dependent manner. Short-term exposure to resveratrol significantly reduced the activation of the HGF-induced c-Met signaling pathway, while long-term exposure markedly decreased c-Met expression on the cell membrane. Additionally, it suppressed HGF-induced cell invasion [80].

3.1.6. Pancreatic Cancer

Ratajczak et al. [81] investigated the effects of resveratrol on three human pancreatic cancer cell lines, EPP85-181P, EPP85-181RNOV (mitoxantrone-resistant), and AsPC-1, as well as the normal pancreatic cell line H6c7. Their findings suggest that it exerts anticarcinogenic effects by inhibiting the proliferation of pancreatic cancer cells and modulating levels of pro- and anti-apoptotic Bcl-2 proteins. Notably, its activity was cell line-specific, with the most significant effects observed in the mitoxantrone-resistant cells. Another study showed that it reduced tumor growth, triggered apoptosis, and increased Bax expression in Capan-2 cells [82]. Qin and his team revealed that nutrient-deprivation autophagy factor-1 (NAF-1) is present in pancreatic cancer tissue and is associated with disease progression. Additionally, they discovered that inhibiting NAF-1 significantly reduces the stem cell properties and invasion and migration capabilities of pancreatic cancer cells [83]. Another study demonstrated that treatment with resveratrol (ranging from 0 to 200 µM) significantly increased the proportion of pancreatic cancer cells (ASPC-1, BXPC-3, Panc-1 cell lines) in the G0/G1 phase of the cell cycle compared to the control group [84,85]. Li et al. [86] showed that resveratrol, applied at concentrations ranging from 0 to 50 µM for 24 h, inhibited the phosphorylation of AKT and NF-κB in BxPC-3 and Panc-1 cells in a dose-dependent manner.

3.2. In Vivo Studies

In vivo studies are essential for comprehending the physiological and therapeutic effects of resveratrol within complex biological systems. These studies provide insights into how it interacts with various pathways and influences disease progression in living organisms, effectively bridging the gap between in vitro research and clinical applications. Multiple animal models, including murine and xenograft models, have been utilized to assess the anticancer effects of resveratrol.

Table 2. Effects of resveratrol against various types of cancer: in vivo studies.

Type of Cancer	Animal Model	Dose	Outcome	References
Colorectal	F344 rats	200 μg/kg/day	Suppresses growth	[87]
	SCID 1 mice	150 mg/kg/day	Suppresses growth	[88]
	Wistar rats	8 mg/kg/day	Inhibits tumorigenesis	[89]
	Sprague–Dawley rats	60 mg/kg/day	Decreases aberrant crypt foci and mucin depleted foci	[90]
Breast	BALB/c mice 2	1, 3, or 5 mg/kh/day	No effect	[91]
	Sprague–Dawley rats	10 or 100 mg/kg/5×/week	Inhibition of carcinogen-induced preneoplastic lesions and mammary tumors	[92]
	HER2/neu mice	4 μg/day	Reduces the metastasizing	[93]
	SCID mice	0.5, 5 or 50 mg/kg/5×/week	Increases tumor growth	[94]
	Nude mice	0.5, 5 or 50 mg/kg/5×/week	Increases tumor growth	[94]
Liver	Wistar rats	20 mg/kg/day	Induces apoptosis	[95]
	HBx mice	30 mg/kg/day	Delayed hepatocarcinogenesis	[96]
	C57BL/6J mice	1 mg/kg/day	Prevention of inflammation-dependent melanoma metastasis	[97]
	Sprague–Dawley rats	0, 100 or 300 mg/kg/day	Prevents chemically induced liver tumorigenesis	[98]
Lung	Nude mice	15, 30, or 60 mg/kg/day	Decreases lung cancer growth in a dose-dependent manner	[99]
	C57B6 mice	25 mg/kg/day	Decreases tumor volume, cell proliferation, tumor angiogenesis and liver metastatic lesions	[100]
	BALB/c nude mice	1 g/kg/day or 3 g/kg/day	Suppresses growth	[101]
	Nude mice	50 mg/kg/day	Suppresses growth	[102]
	C57B6 mice	100 mg/kg/day	Decreases F4/80+ macrophage	[103]
Prostate	Nude mice	50 mg/kg/day	Suppresses growth	[104]
	TRAP rats	0.005, 0.01, or 0.02%/day	Suppresses growth	[71]
	TRAMP mice	0.0625%/day	Suppresses growth	[105]
Pancreatic	Nude mice	20, 40, or 60 mg/kg/day	Suppresses growth	[106]
	KrasG12D mice	40 mg/kg/5×/week	Inhibits pancreatic cancer stem cell	[107]
	Nude mice	10 or 50 mg/kg/5×/week	Suppresses growth	[108]
	Nude mice	40 mg/kg/day	Potentiate the effects of gemcitabine	[109]

¹ severe combined immunodeficiency; ² Bagg Albino/c.

highlights the diverse effects of resveratrol observed in vivo, such as its capacity to reduce oxidative stress, inhibit tumor growth, and improve cardiovascular health. These effects are attributed to its interaction with key signaling pathways and its ability to modulate gene expression and inflammatory responses.

In a subcutaneous xenograft model of pancreatic cancer in nude mice, resveratrol was administered at a dose of 50 mg/kg daily for six weeks. This treatment resulted in the suppression of NAF-1 expression, which correlated with a significant reduction in tumor growth. These findings suggest that it acts as an effective anti-tumor agent, potentially targeting NAF-1 as a therapeutic approach [83]. Another study investigated its impact and nanoformulation (NP-RSV) on tumor growth and vascularity in colon cancer models using both xenograft and orthotopic mice. Mice treated with resveratrol at 100 mg/kg and NP-RSV at an equivalent dose showed significant reductions in tumor growth and hemoglobin content within the tumor mass, indicating decreased vascularity and improved therapeutic efficacy of NP-RSV compared to resveratrol alone [110]. These studies collectively highlight its potential as an adjunctive therapy in cancer treatment. The observed anti-tumor effects, particularly when combined with nanoformulation techniques, underscore the importance of further exploring its mechanisms of action and its application in clinical settings. Future research should focus on optimizing dosage regimens, understanding long-term effects, and exploring synergistic combinations with other therapeutic agents.

A search for “resveratrol and cancer” on Clinicalrials.gov reveals only 18 studies, with some focusing primarily on resveratrol’s pharmacokinetics rather than its therapeutic effects (

Table 3. Clinical trials involving resveratrol against types of cancer.

Type of Cancer	Clinical Trial	Status	Study ID (https://clinicaltrials.gov) Accessed on 31 July 2024
Colorectal	Phase 1	Completed (2009)	NCT00920803
	Phase 1	Completed (2009)	NCT00433576
	Phase 1	Completed (2007)	NCT00578396
Neuroendocrine Tumor	N.A *	Completed (2018)	NCT01476592
Liver	Phase 1/2	Completed (2016)	NCT02261844
Colon	Phase 1	Completed (2009)	NCT00256334
Multiple Myeloma	Phase 2	Completed (2010)	NCT00920556

* Not applicable.

). This limited number of clinical trials raises concerns about the practicality of resveratrol as a cancer treatment.

While the clinical trials summarized in Table 2 indicate the potential of resveratrol as an adjunct therapy in cancer treatment, it is crucial to acknowledge certain limitations that may impact its clinical application. Despite the promising preclinical data, challenges such as small-scale trials and variability in study design complicate our understanding of its therapeutic potential. These factors highlight the need for larger, more comprehensive studies to fully explore its efficacy in conjunction with established therapeutic agents.

4. Resveratrol in Combination with Other Treatments

4.1. Chemotherapy

Resveratrol has attracted considerable interest as a potential adjunct in cancer therapy, especially when paired with conventional chemotherapy. This interest is driven by its ability to both enhance the effectiveness of chemotherapeutic agents and mitigate their common side effects, which can limit the broad application of these treatments in clinical settings.

A major concern in cancer treatment is cardiotoxicity, a common side effect of many chemotherapeutic agents [111]. Commonly used anthracyclines like doxorubicin often result in severe cardiotoxic effects, including myocarditis, arrhythmias, dilated cardiomyopathy, and congestive heart failure [112]. These adverse effects are linked to the production of free radicals and oxidative stress, as doxorubicin increases ROS formation in heart tissues [113,114]. A study by Sheu and his team examined the antioxidant effects of four different compounds, including resveratrol, and found that co-treatment with doxorubicin significantly reduced intracellular ROS levels while increasing SOD levels, which are involved in eliminating ROS. Among the antioxidants tested, resveratrol was the most effective at neutralizing ROS, suggesting its potential as a supplement to mitigate doxorubicin-induced cardiotoxicity [115]. Additionally, Ito et al. [116] found that resveratrol and its analogs can bind to carbonyl reductase 1 (CBR1), inhibiting its activity and thereby reducing doxorubicin’s cardiotoxicity. Arsenic trioxide (As₂O₃), another traditional anticancer drug primarily used for treating acute promyelocytic leukemia (APL), also causes adverse effects such as cardiotoxicity. Like anthracyclines, the primary pathogenic mechanism of As₂O₃ is associated with oxidative stress [117,118]. Zhao et al. [119] reported that pre-treatment with resveratrol (3 mg/kg) one hour before As₂O₃ administration could protect against As₂O₃-induced cardiotoxicity and reduce myocardial injury, oxidative damage, and DNA fragmentation.

In addition to cardiotoxicity, chemotherapy often leads to gastrointestinal side effects including anorexia, nausea, vomiting, constipation, and diarrhea [120]. Ko et al. [121] demonstrated that pretreating Wistar rats with whole grape juice, which contains high levels of resveratrol could promote gastric emptying and improve tubular dilation and vacuolization in renal tubules, thereby helping to prevent cisplatin-induced gastrointestinal disorders.

In addition to mitigating adverse effects, resveratrol shows promise in enhancing the efficacy of various chemotherapeutic agents. For example, it has shown synergistic effects with 5-fluorouracil (5-FU) and doxorubicin, enhancing their antitumor efficacy in colorectal [122] and oral [123] cancer types. Hu et al. [122] highlighted the therapeutic potential of resveratrol, particularly when combined with ginkgetin and 5-FU. This combination suppressed the expression of COX-2 and inflammatory cytokines, alleviating the inflammatory response induced by 5-FU. Additionally, ginkgetin and resveratrol inhibit VEGF-induced endothelial cell proliferation, migration, invasion, and angiogenesis. Another study by Kong et al. [124] found that combining 5 μg/mL or 10 μg/mL resveratrol with 5 μg/mL paclitaxel resulted in greater growth inhibition and apoptosis of the A549 NSCLC cell line compared to treatment with each agent alone. This combination treatment notably downregulated mRNA and protein levels of several key molecules associated with cancer progression, such as COX-2, VEGF, and various matrix metalloproteinases (MMPs), as well as anti-apoptotic proteins like Bcl-2 and Bcl-xL. Additionally, it reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β) and iNOS, while enhancing the expression of anti-cancer genes, including tissue inhibitors of metalloproteinases (TIMPs), IκB-α, p53, p21, and pro-apoptotic proteins. The synergy between resveratrol and cisplatin is particularly notable in reducing metastasis. This combination not only inhibits cell proliferation and invasion but also reduces telomerase activity and enhances ß-galactosidase activity. It induces cell cycle arrest at the G0/G1 phase, promotes apoptosis, and supports cell senescence through the P38/P53 and P16/P21 pathways [125]. Additionally, resveratrol and cisplatin together induce endoplasmic reticulum stress-mediated apoptosis and cause cell cycle arrest at the G2/M phase in gastric cancer cells [126]. Resveratrol has demonstrated significant potential as an adjunct therapy in osteosarcoma treatment, enhancing the effects of conventional chemotherapy regimens [127].

Overall, resveratrol has demonstrated substantial potential as an adjunct therapy in cancer treatment, particularly when combined with conventional chemotherapy regimens. Its ability to enhance the efficacy of various chemotherapeutic agents while mitigating their adverse effects highlights its promise as a valuable therapeutic agent in the fight against cancer.

4.2. Radiotherapy

Resveratrol shows promise as an adjunct treatment in cancer therapy when combined with radiotherapy. Radiotherapy is a standard cancer treatment that uses ionizing radiation to kill cancer cells [128]. However, it can also harm surrounding normal tissues, leading to adverse side effects. Resveratrol enhances the efficacy of radiotherapy while protecting normal cells from radiation-induced damage, making it an attractive candidate for combination therapy [129].

A key benefit of combining resveratrol with radiotherapy is its ability to reduce oxidative stress and protect normal cells from apoptosis [130]. This protective effect is mediated through the activation of the SIRT1/FOXO3a and PI3K/Akt pathways, which help in reducing radiation-induced intestinal damage [131]. Additionally, it has been found to increase the tumor cell sensitivity to radiation and increase apoptosis. Its radio-sensitizing effects are attributed to its ability to disrupt DNA repair mechanisms early on, inhibit cell proliferation, induce autophagy and promote apoptosis in both laboratory and animal models [132].

In addition to its radioprotective properties, numerous studies have demonstrated resveratrol’s synergistic effects when combined with ionizing radiation [133,134,135]. Although the radiosensitizing effects of resveratrol are well documented in vitro, only a few in vivo studies have confirmed its ability to enhance the effectiveness of radiotherapy. One study identified that its radiosensitizing mechanism involves increased autophagy and apoptosis [132]. Another study by Mikami et al. [136] demonstrated that it enhances irradiation efficacy via the expression pathway of the regenerating gene (REG) III. Furthermore, a study investigating the effects of radiotherapy combined with resveratrol on radioresistant glioma stem cells (GSCs) found that it inhibited GSC proliferation and enhanced radiosensitivity. This combination treatment decreased the expression of the neural stem cell marker CD133, induced cell differentiation, and significantly increased levels of autophagy and apoptosis both in vitro and in vivo [132]. Additional research suggests that resveratrol, when used in combination with ionizing radiation, delays the repair of radiation-induced DNA double-strand breaks (DSBs) and prolongs G2/M cell cycle arrest, leading to increased apoptosis [137].

4.3. Target Therapies and Immunotherapy

Resveratrol’s ability to modulate signaling pathways and immune responses suggests potential benefits when used alongside targeted therapies and immunotherapies.

Targeted therapies are designed to interfere with specific molecules involved in cancer growth and progression [138]. These therapies aim to selectively target cancer cells while sparing normal cells, offering a more precise approach compared to traditional chemotherapy [139]. Resveratrol has been studied for its ability to enhance the effects of targeted therapies through some mechanisms. One significant mechanism is the inhibition of key signaling pathways, such as the PI3K/Akt/mTOR pathway, a critical signaling cascade that is frequently overactive in various cancers, contributing to tumor growth and survival [140]. By downregulating this pathway, resveratrol can promote apoptosis and inhibit cancer cell proliferation, as observed in studies involving glioma cells, where it not only reduces Akt activation but also decreases the phosphorylation of downstream targets like S6 kinase [43]. Studies have shown that it can potentiate the effects of tyrosine kinase inhibitors, leading to increased cancer cell apoptosis and reduced proliferation [141]. Moreover, it has been shown to modulate the expression of key proteins involved in cell survival and apoptosis, such as Bcl-xL and Bax. For example, resveratrol enhances the effectiveness of trastuzumab through synergistic interactions that notably reduce Bcl-xL gene expression and increase apoptosis in breast cancer cells [142]. Another significant challenge in cancer treatment is overcoming drug resistance. Resveratrol modulates molecular pathways that help to counteract multidrug resistance (MDR), including the downregulation of proteins such as P-glycoprotein (P-gp) [143] and multidrug-resistance-associated proteins (MRPs) [144], often overexpressed in resistant cancer cells. By modulating these pathways, it enhances the sensitivity of cancer cells to targeted therapies, making it a valuable adjunct in treatment regimens [145].

Immunotherapy has revolutionized cancer treatment by harnessing the immune system to identify and eradicate cancer cells [146]. However, its efficacy may be compromised by the immunosuppressive tumor microenvironment and the ability of cancer cells to evade immune detection [147]. Resveratrol’s diverse biological activities may enhance immunotherapy’s effectiveness in several ways. Firstly, it modulates the immune response by enhancing the activity of various immune cells, including T cells, natural killer (NK) cells, and dendritic cells [148]. By boosting the function of these immune cells, it may augment the effectiveness of immunotherapies, such as checkpoint inhibitors, which depend on an active immune response to target cancer cells [149]. Secondly, chronic inflammation within the tumor microenvironment can suppress the immune response against cancer’s [150] anti-inflammatory properties, mediated through the inhibition of NF-κB signaling and the reduction in pro-inflammatory cytokines, creating a more favorable environment for immunotherapy to operate [13,40]. By mitigating inflammation, it enhances the infiltration and activity of immune cells in tumors. Additionally, checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 pathways have shown substantial success in treating specific cancers, but not all patients respond favorably [149,151,152,153]. Resveratrol has been shown to downregulate the expression of PD-L1 in cancer cells, which can potentiate the efficacy of PD-1/PD-L1 inhibitors [154,155]. This synergistic effect could improve the response rates and outcomes for patients undergoing checkpoint inhibitor therapy. Moreover, inducing immunogenic cell death is an objective of cancer therapy, where dying cancer cells release signals that attract and activate immune cells [156]. Resveratrol has been shown to induce such immunogenic cell death, enhancing the immune system’s ability to recognize and attack cancer cells [157]. This property positions resveratrol as a promising candidate for combination with immunotherapy. Lastly, some tumors develop resistance to immunotherapy by creating an immunosuppressive microenvironment or upregulating immune checkpoints [158]. Resveratrol’s ability to modulate multiple pathways involved in immune evasion and suppression may help to overcome these resistance mechanisms, enhancing the efficacy of immunotherapy [159,160,161].

5. Adverse Effects and Safety Considerations

Although resveratrol is widely recognized for its therapeutic potential and general safety, its use at higher therapeutic doses may be associated with adverse effects and safety concerns [162]. Commonly reported side effects include gastrointestinal disturbances such as nausea, diarrhea, and abdominal pain, which are often dose-dependent and may become more pronounced at elevated doses [163]. Resveratrol has also been linked to hepatotoxicity, with some studies suggesting that high doses may adversely affect liver function [162]. While such effects are relatively rare, monitoring liver health is advisable, especially for individuals with pre-existing liver conditions or those on other medications that affect liver function.

Drug interactions are another area of concern; resveratrol may influence the metabolism of medications processed by the liver’s cytochrome P450 enzymes, potentially altering the efficacy and safety of concomitant therapies [164]. This is especially pertinent for patients on anticoagulants or antiplatelet medications, as resveratrol may enhance the risk of bleeding [165,166].

Particular caution is advised for patients with hormone-responsive cancers, such as breast cancer, due to resveratrol’s influence on hormone signaling pathways. Resveratrol may exhibit estrogenic effects, which could potentially affect hormone-driven tumor growth [167,168].

To ensure safe and effective use, comprehensive safety evaluations are essential, necessitating thorough clinical trials to establish appropriate dosing regimens and identify potential adverse effects [169]. Optimal dosing should balance therapeutic benefits with minimal side effects, and regular monitoring of liver function and gastrointestinal health should be included in the management strategy. Patients should consult their healthcare providers before initiating resveratrol supplementation, especially if they are on other medications or have underlying health conditions.

6. Limitations of Current Studies

Although preclinical data highlight resveratrol’s potential as a cancer therapeutic, several limitations must be addressed before its clinical application can be fully realized. One of the major challenges is its poor bioavailability [170]. Resveratrol is rapidly metabolized and eliminated from the body, resulting in low and fluctuating plasma levels that are often insufficient to achieve the therapeutic concentrations needed for effective cancer treatment [171]. This challenge complicates the ability to maintain adequate drug levels in target tissues.

Additionally, variability in the study results adds further complexity. While some preclinical studies show significant anticancer effects and enhanced apoptosis in various cancer cell lines, others report inconsistent or modest results. Differences in study design, dosage, formulation, and methodologies contribute to this variability, making it difficult to generalize findings across different models and cancer types.

The clinical trial landscape also reveals limitations regarding the use of resveratrol as a cancer therapy. Currently, most clinical trials are small-scale and often focus on resveratrol’s bioavailability and pharmacokinetics rather than its direct anti-cancer effects. This disparity between preclinical success and clinical application highlights the urgent need for larger, more comprehensive trials to fully elucidate the therapeutic potential of resveratrol in cancer treatment.

In addition, formulation and delivery issues present a significant challenge. Resveratrol’s low bioavailability requires the development of advanced delivery systems to enhance its stability and effectiveness. Nanoparticle-based and liposomal formulations are being explored, but their success and safety require thorough validation.

Furthermore, a detailed understanding of the molecular mechanisms through which resveratrol acts is still evolving. This knowledge is crucial for optimizing dosing strategies and predicting patient responses. Without clear insights into its mechanisms of action, determining the most effective treatment regimens and identifying appropriate patient populations remains challenging.

Lastly, while resveratrol is generally considered safe, its potential side effects and interactions with other medications must be carefully evaluated. Managing these factors is essential to ensuring that resveratrol can be used safely and effectively in cancer treatment.

7. Future Perspectives

The exploration of resveratrol’s role in cancer therapy offers numerous promising research avenues. As studies continue to assess its potential to enhance the efficacy of traditional chemotherapeutic agents and mitigate their adverse effects, it becomes increasingly important to deepen our understanding of its mechanisms and optimize its application. Future research should not only focus on elucidating the precise pathways through which resveratrol improves treatment outcomes and reduces side effects, but also emphasize the need to first understand these mechanisms individually before exploring their combined effects with other therapies. This includes a detailed examination of its effects on various signaling pathways, gene expression, and cellular processes involved in cancer progression and drug resistance.

Optimizing the dosage and administration of resveratrol is crucial to harness its full therapeutic potential. Investigating the most effective dosages and delivery methods will help to maximize the benefits of resveratrol while minimizing potential toxicity. Additionally, further research into combining resveratrol with other emerging therapies should be carefully designed to reveal potential synergistic effects while also considering the complexities of how these therapies may interact on a molecular level. Exploring its interactions with targeted therapies, immunotherapies, and novel small molecules could provide valuable insights into developing more effective combination treatments. However, it is essential to first elucidate resveratrol’s isolated mechanisms of action before fully understanding its role in combination therapies.

Expanding the scope of research to include a wider range of cancer types will be essential. While current studies have focused on specific cancers, there is significant potential to investigate resveratrol’s effects across other malignancies, including those resistant to conventional treatments. This broader exploration could uncover new therapeutic applications and improve outcomes for a wider range of cancer patients.

To transition from preclinical findings to clinical practice, well-designed clinical trials are necessary. These trials should be meticulously planned to evaluate the safety, efficacy, and optimal dosing of resveratrol in combination with standard chemotherapies. Randomized, controlled trials will provide robust data on treatment outcomes and help identify which patient populations are most likely to benefit. Identifying biomarkers that predict patient response to resveratrol-based therapies will also be important for personalizing treatment and improving patient outcomes.

Long-term follow-up in clinical trials will be crucial to assess the durability of therapeutic responses, monitor long-term side effects, and evaluate the overall impact on patients’ quality of life. Navigating regulatory pathways to facilitate the approval of resveratrol-based therapies will require addressing safety concerns, standardizing formulations, and ensuring compliance with clinical trial regulations.

In conclusion, while the current research on resveratrol is promising, advancing this work involves exploring new research directions, developing innovative combined treatments, and conducting rigorous clinical trials. By addressing these areas, the potential for resveratrol to significantly impact cancer therapy can be realized, ultimately improving treatment outcomes and enhancing patient quality of life.

8. Conclusions

Resveratrol, a naturally occurring polyphenolic compound, has demonstrated significant potential in cancer management through its multifaceted mechanisms of action. Its antioxidant, anti-inflammatory, antiproliferative and epigenetic modulation properties provide a strong foundation for its application in cancer therapy. In vitro and in vivo studies have consistently shown its efficacy in inhibiting cancer cell growth, inducing apoptosis and enhancing the effects of conventional treatments such as chemotherapy and radiotherapy. However, despite these promising findings, the clinical translation of resveratrol is challenged by issues related to its bioavailability and potential toxicity. Future research should focus on optimizing delivery methods, understanding the long-term effects, and conducting comprehensive clinical trials to fully realize its therapeutic potential in cancer treatment.