Resveratrol: Its wide range of potential anticancer effects
Resveratrol, a polyphenol found in various plants including grapes, berries, and peanuts, has gained attention in cancer research due to its wide range of potential anticancer effects. The mechanisms through which resveratrol impacts cancer cells are multifaceted, affecting various aspects of cancer biology. Its role in cancer can be particularly insightful when examined from the perspectives of the metabolic theory of cancer and the mutated stem cell theory.
The growing interest in complementary cancer treatments reflects patients’ and caregivers’ desire to look beyond standard therapies alone. Natural polyphenols like resveratrol have attracted attention based on extensive preclinical anti-cancer effects. However, leveraging natural substances like resveratrol in mainstream oncology has complexities.
Rigorously validating resveratrol’s efficacy, especially in human trials, is still being pursued. While cell culture and animal model experiments demonstrate anticancer potential through diverse mechanisms, translating these to clinical applications requires substantial research investment. Unfortunately, as a common non-patentable molecule, limited profit potential constraints private funding for comprehensive human studies. This economic reality hinders progress.
Still, the accumulating research suggests multimodal anticancer actions for resveratrol on molecular processes underlying cancer initiation and progression. Unlike targeted chemotherapy drugs, resveratrol may influence broader cellular networks – metabolism, proliferation, inflammation, and apoptosis. An exciting frontier is synergism between resveratrol and chemotherapy, potentially mitigating toxicity.
Definitive clinical translation remains a key barrier. But resveratrol’s observed antiproliferative, pro-apoptotic, anti-inflammatory, anti-angiogenic, and chemosensitizing preclinical effects continue catalyzing interest in oncology. Impact likely hinges on economical human trials and strategic integration with mainstay cancer therapies. Even if not a stand-alone targeted agent, resveratrol warrants closer exploration as a complementary adjuvant expanding therapeutic options.
Mechanisms of Resveratrol's Anticancer Effects
From the perspective of the metabolic theory of cancer, resveratrol's impact is particularly significant in the context of how it influences the energy metabolism of cancer cells. This theory posits that cancer is largely a metabolic disease, characterized by altered energy production, primarily through glycolysis even in the presence of oxygen (known as the Warburg effect). Resveratrol targets these altered metabolic pathways, disrupting the cancer cells' reliance on glycolysis for energy. By interfering with this preferential metabolic pathway, resveratrol can impede the rapid growth and proliferation of cancer cells. Additionally, it affects mitochondrial function, which is crucial for energy production and cellular signaling in cancer cells. Mitochondria in cancer cells often function differently from those in normal cells, and by targeting these organelles, resveratrol can further disrupt the cancer cells' metabolic balance, potentially leading to reduced viability and growth of the tumor cells.
Resveratrol's role in cancer metabolism extends to the modulation of key metabolic enzymes and signaling pathways involved in cancer cell growth and survival. It can inhibit enzymes that are overactive in cancer cells, such as those involved in aerobic glycolysis, and influence signaling pathways like AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). These pathways are integral to cellular growth and energy balance, and their modulation by resveratrol can lead to a reduction in energy availability for cancer cells, hampering their proliferation. This metabolic interference not only starves cancer cells of the energy they need for rapid growth but also can trigger apoptotic pathways, leading to programmed cell death. Through these multifaceted interactions with cancer cell metabolism, resveratrol emerges as a potential agent that can exploit the metabolic vulnerabilities of cancer cells, offering a novel approach to cancer therapy that complements the traditional focus on genetic mutations and cellular signaling.
Resveratrol and the Mutated Stem Cell Theory:
The mutated stem cell theory of cancer suggests that the disease originates from a subset of cells, known as cancer stem cells, which have undergone genetic mutations. These cells are believed to be responsible for the initiation, maintenance, and recurrence of cancer. Resveratrol's interaction with this aspect of cancer biology is noteworthy. It targets and modulates the pathways that are crucial for maintaining the unique properties of these cancer stem cells, such as self-renewal and differentiation. By influencing these pathways, resveratrol can disrupt the fundamental processes that these mutated stem cells use to drive tumor growth and metastasis. For instance, resveratrol has been shown to downregulate the expression of key stemness factors such as Nanog and Oct-4, which are vital for the maintenance of stem cell properties in cancer cells. Additionally, it impacts signaling pathways like Wnt/beta-catenin and Hedgehog, which are often aberrantly activated in cancer stem cells, contributing to their malignant behavior.
The ability of resveratrol to induce differentiation of cancer stem cells into more differentiated, non-stem cancer cells presents a significant therapeutic advantage. This process of differentiation effectively strips these cells of their stem-like properties, rendering them less aggressive and more susceptible to conventional cancer therapies. Resveratrol's role in altering the cell division kinetics of cancer stem cells leads to this shift in their state, reducing their ability to contribute to tumor progression and resistance to treatment. This action of resveratrol addresses one of the major challenges in cancer treatment - the eradication of cancer stem cells, which are often resistant to standard therapies and are implicated in cancer recurrence and metastasis. By targeting these cells and their unique properties, resveratrol adds a critical dimension to cancer therapy, potentially enhancing the overall effectiveness of treatment regimens and reducing the likelihood of cancer recurrence.
Effects of Resveratrol on Cancer Cell Biology
Proliferation - Resveratrol inhibits cell division and proliferation in various cancer cell lines such as breast, liver, colorectal by regulating cell cycle proteins, cyclins, and cyclin-dependent kinases. This anti-proliferative effect stems from growth signaling blockade.
Apoptosis - It promotes programmed cancer cell death (apoptosis) through p53 activation, increased Bax/Bcl-2 ratio, caspase activation, and cytoplasmic histone-associated DNA fragmentation.
Angiogenesis - Resveratrol prevents new blood vessel formation (angiogenesis) by cancer cells, which limits nutrient supply to tumors. It suppresses vascular endothelial growth factor (VEGF) and metalloproteinases to inhibit angiogenesis.
Metastasis - It reduces metastasis by inhibiting epithelial-to-mesenchymal transition (EMT), cancer cell motility, and expression of adhesion molecules involved in migration/invasion through tissue.
Drug resistance - It can overcome chemotherapy resistance by inhibiting transporters like MRP1 that remove drug from cells and enhancing apoptosis.
Inflammation - Resveratrol exhibits potent anti-inflammatory effects by reducing pro-inflammatory mediators like NF-kB, TNF-alpha, IL-6, and COX and suppressing inflammatory enzyme expression. This attenuates carcinogenesis.
It activates AMPK, which acts as an energy sensor in cells, while inhibiting mTOR signaling, suppressing glycolysis and redirecting metabolism away from cell growth pathways.
It reduces glucose uptake via GLUT transporters and decreases aerobic glycolysis (Warburg effect) relied upon by cancer cells, compromising their energy sources.
Exhibits the ability to enhance mitochondrial respiration in cancer cells, leading to an increased production of reactive oxygen species (ROS) andl can induce oxidative stress in cancer cells, impairing their growth and potentially triggering cell death pathways.
By targeting cancer cell metabolism through these mechanisms, resveratrol restricts energy, nutrients and redox control needed for excessive proliferation.
Impacts key regulatory pathways in cancer stem cells by suppressing the expression of stemness factors such as Nanog, Oct-4, as well as signaling pathways like Hedgehog and Wnt/beta-catenin. These factors and pathways are crucial in maintaining the growth and self-renewal capabilities of cancer stem cells.
It has been observed to inhibit sphere formation in these cells, a process indicative of the self-renewal capacity of stem cells, which is crucial for the perpetuation and spread of cancer. This inhibition of self-renewal by resveratrol disrupts the cancer stem cells' ability to initiate and maintain tumor growth.
Demonstrates a significant capacity to sensitize cancer stem cells to conventional cancer treatments like chemotherapy and radiotherapy. It enhances the efficacy of these treatments by increasing DNA damage in cancer stem cells, a crucial mechanism through which radiotherapy and chemotherapy exert their effects. Additionally, resveratrol aids in promoting cell death (apoptosis) in these treatment-resistant cells.
Plays a role in inducing differentiation of cancer stem cells into non-stem cancer cells. This process, driven by alterations in cell division kinetics, shifts cancer stem cells from a state of self-renewal to one where they adopt characteristics of more differentiated, less aggressive cancer cells
Resveratrol exhibits anti-cancer activity through a variety of interconnected cellular mechanisms:
Anti-inflammatory Effects:
Resveratrol reduces chronic inflammation that promotes cancer development by downregulating inflammatory mediators like NF-kB, COX-2, TNF-alpha, and interleukin proteins. This anti-inflammatory activity is believed to contribute to its cancer prevention and therapeutic potential.
Anti-oxidant Properties:
It acts as a free radical scavenger to attenuate DNA damage from reactive oxygen species that can cause tumor-driving mutations. Its antioxidant effects protect cell integrity.
Pro-apoptotic Action:
Resveratrol can trigger programmed cancer cell death (apoptosis) through multiple pathways - activating p53, caspases, apoptosis inducing receptors on the cell surface, and pro-apoptotic proteins.
Anti-proliferative Effects:
It blocks abnormal cancer cell division and growth by regulating key cell cycle control proteins, halting progression through cell cycle phases. It also inhibits growth factor signaling through pathways like Wnt/Beta-catenin.
Prevents the development of new blood vessels (angiogenesis) to supply tumors with oxygen and nutrients needed to proliferate. It reduces vascular endothelial growth factor (VEGF).
It enhances anti-cancer immune surveillance by stimulating natural killer cell cytotoxicity against tumor cells. Resveratrol may also inhibit immunosuppressive effects of myeloid derived suppressor cells.
Through these convergent effects - decreasing inflammation, oxidative stress, growth signaling, angiogenesis and immune evasion while increasing apoptosis - resveratrol acts through diverse molecular pathways to inhibit cancer development and progression.
Let's take these perspectives a little bit further in terms of resveratrol's potential effect on cancer initiation and proliferation.
Stimulation of Natural Killer (NK) Cell Activity:
NK cells are a type of lymphocyte (a white blood cell) and a component of the innate immune system. They play a crucial role in the body's first line of defense against tumors and virally infected cells.
Resveratrol can enhance the cytotoxicity of NK cells. This enhancement means that NK cells are more effective in identifying and destroying tumor cells.
The mechanism involves the upregulation of activating receptors on NK cells, such as NKG2D, which recognize stress-induced molecules on the surface of tumor cells.
Resveratrol may also increase the production of cytokines like interferon-gamma (IFN-γ), which are crucial for NK cell activation and function.
Modulation of Cytokine Production:
Resveratrol can influence the production of cytokines, which are small proteins important in cell signaling.
It can promote the production of pro-inflammatory cytokines, which are essential for initiating effective immune responses against cancer cells.
Conversely, it may also suppress the production of anti-inflammatory cytokines, which can be beneficial in the context of cancer, as some tumors utilize anti-inflammatory pathways to evade immune detection.
Inhibition of Myeloid-Derived Suppressor Cells (MDSCs):
MDSCs are a heterogeneous population of immune cells that expand in cancer, inflammation, and infection. They are known for their immunosuppressive effects, which include inhibiting T-cell activation and proliferation.
Resveratrol can inhibit the function and development of MDSCs, thereby reducing their immunosuppressive effects.
The compound may interfere with signaling pathways that are crucial for the survival and function of MDSCs, such as the STAT3 signaling pathway.
By inhibiting MDSCs, resveratrol can potentially restore the function of various immune cells, including T cells and NK cells, enhancing the body's anti-tumor immune response.
Direct Effects on Tumor Cells:
Apart from modulating immune cells, resveratrol can exert direct anti-proliferative effects on tumor cells.
It can induce apoptosis (programmed cell death) in cancer cells and inhibit their proliferation and invasion.
Enhancement of Antigen Presentation:
Resveratrol may enhance the process of antigen presentation, a key step in activating the adaptive immune response.
By improving the presentation of tumor antigens, it can help in the more effective activation of T cells, which are critical for targeting and destroying cancer cells.
Enhance Absorption and Utilization
At times the criticism of resveratrol has been that it has somewhat limited bioavailability. It does turn out that there are a number of things they can substantially enhance its absorption and utilization:
Dietary Fats/Oils:
Taking resveratrol alongside oils or other dietary fats has been shown to increase absorption. Lipids stimulate bile release which may improve solubility and gastrointestinal uptake of resveratrol.
Specific oils like olive oil, corn oil and emulsified forms have demonstrated an ability to enhance systemic exposure and peak plasma levels of resveratrol in studies.
The bioavailability increase with oils is likely tied to facilitated micellar solubilization allowing more efficient absorption.
However, high fat meals may also influence metabolism, for example shifting conjugation towards sulfate forms over glucuronides based on some studies.
Piperine:
Piperine, a compound from black pepper, has been shown to significantly enhance serum levels of resveratrol when co-supplemented by inhibiting glucuronidation metabolism.
One study found an over 200% increase in resveratrol bioavailability with piperine co-administration compared to resveratrol alone.
Quercetin:
The flavonoid quercetin may also increase bioavailability of resveratrol by slowing its metabolism, based on evidence from preclinical studies.
Strategic co-supplementation with dietary fats/oils, piperine or quercetin holds promise as methods for increasing the bioavailability and absorption of resveratrol to boost its systemic effects.
As we can readily see here, resveratrol deserves much more in-depth exploration in regards to its possible use in human cancers. There's much to suggest that it may be very helpful in enhancing the treatment and the outcomes of a variety of cancers. The challenge is to find the funding to support these studies as there is not a great profit motive to drive this research.
https://www.sciencedirect.com/science/article/pii/S030438352100197X?via%3Dihub