Cancer:
Breast, lymphoma, breast, gastric, colorectal, esophageal, prostate, pancreatic, leukemia, skin, lung
Action: Chemoprevention, anti-inflammatory, MDR, chemotherapy-induced cytotoxicity, radio-sensitizer, enhances chemo-sensitivity
Resveratrol (RSV) is a phytoalexin found in food products including berries and grapes, as well as plants (including Fallopia japonica (Houtt.), Gnetum cleistostachyum (C. Y. Cheng), Vaccinium arboretum (Marshall), Vaccinium angustifolium (Aiton) and Vaccinium corymbosum (L.)
Although resveratrol is ubiquitous in nature, it is found in a limited number of edible substances, most notably in grapes. In turn, due to the peculiar processing methodology, resveratrol is found predominantly in red wines. Thus, resveratrol received intense and immediate attention. A large number of resveratrol anti-cancer activities were reported, affecting all the steps of cancerogenesis, namely initiation, promotion, and progression. Thereafter, an exponential number of reports on resveratrol accumulated and, so far, more than 5,000 studies have been published (Borriello et al., 2014).
Up to the end of 2011, more than 50 studies analyzed the effect of resveratrol as an anti-cancer compound in animal models of different cancers, including skin cancer (non-melanoma skin cancer and melanoma); breast, gastric, colorectal, esophageal, prostate, and pancreatic cancers; hepatoma, neuroblastoma, fibrosarcoma, and leukemia (Ahmad et al., 2004; Hayashibara et al., 2002; Pozo-Guisado et al., 2005; Mohan et al., 2006; Tang et al., 2006). In general, these preclinical studies suggest a positive activity of the molecule in lowering the progression of cancer, reducing its dimension, and decreasing the number of metastases (Vang et al., 2011).
Breast
Resveratrol was shown to have cancer chemo-preventive activity in assays representing three major stages of carcinogenesis. It has been found to mediate anti-inflammatory effects and inhibit cyclooxygenase and hydroperoxidase functions (anti-promotion activity). It has also been found to inhibit the development of pre-neoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model (Jang et al., 1997).
In addition, resveratrol, a partial ER agonist itself, acts as an ER antagonist in the presence of estrogen leading to inhibition of human breast cancer cells (Lu et al., 1999).
Besides chemo-preventive effects, resveratrol appears to exhibit therapeutic effects against cancer itself. Limited data in humans have revealed that RSV is pharmacologically safe (Aggarwal et al., 2004).
Chemotherapy-Induced Cytotoxicity
RSV markedly enhanced Dox-induced cytotoxicity in MCF-7/adr and MDA-MB-231 cells. Treatment with a combination of RSV and Dox significantly increased the cellular accumulation of Dox by down-regulating the expression levels of ATP-binding cassette (ABC) transporter genes, MDR1, and MRP1. Further in vivo experiments in the xenograft model revealed that treatment with a combination of RSV and Dox significantly inhibited tumor volume by 60%, relative to the control group.
These results suggest that treatment with a combination of RSV and Dox would be a helpful strategy for increasing the efficacy of Dox by promoting an intracellular accumulation of Dox and decreasing multi-drug resistance in human breast cancer cells (Kim et al., 2013).
Radio-sensitizer/Lung Cancer
Previous studies indicated that resveratrol (RV) may sensitize tumor cells to chemotherapy and ionizing radiation (IR). However, the mechanisms by which RV increases the radiation sensitivity of cancer cells have not been well characterized. Here, we show that RV treatment enhances IR-induced cell killing in non-small-cell lung cancer (NSCLC) cells through an apoptosis-independent mechanism. Further studies revealed that the percentage of senescence-associated β-galactosidase (SA-β-gal)-positive senescent cells was markedly higher in cells treated with IR in combination with RV compared with cells treated either with IR or RV alone, suggesting that RV treatment enhances IR-induced premature senescence in lung cancer cells.
Collectively, these results demonstrate that RV-induced radio-sensitization is associated with significant increase of ROS production, DNA-DSBs and senescence induction in irradiated NSCLC cells, suggesting that RV treatment may sensitize lung cancer cells to radiotherapy via enhancing IR-induced premature senescence (Luo et al., 2013).
Lymphoma
Ko et al. (2011) examined the effects of resveratrol on the anaplastic large-cell lymphoma (ALCL) cell line SR-786. Resveratrol inhibited growth and induced cellular differentiation, as demonstrated by morphological changes and elevated expression of T cell differentiation markers CD2, CD3, and CD8. Resveratrol also triggered cellular apoptosis, as demonstrated by morphological observations, DNA fragmentation, and cell-cycle analyzes. Further, the surface expression of the death receptor Fas/CD95 was increased by resveratrol treatment. Our data suggest that resveratrol may have potential therapeutic value for ALCL.
Skin Cancer
Treatment with combinations of resveratrol and black tea polyphenol (BTP) also decreased expression of proliferating cell nuclear antigen in mouse skin tissues/tumors than their solitary treatments as determined by immunohistochemistry. In addition, histological and cell death analysis also confirmed that resveratrol and BTP treatment together inhibits cellular proliferation and markedly induces apoptosis. Taken together, results for the first time lucidly illustrate that resveratrol and BTP in combination impart better suppressive activity than either of these agents alone and accentuate that development of novel combination therapies/chemo-prevention using dietary agents will be more beneficial against cancer (George et al., 2011).
Prostate Cancer
Resveratrol-induced ROS production, caspase-3 activity and apoptosis were inhibited by N-acetylcysteine. Bax was a major pro-apoptotic gene mediating the effects of resveratrol as Bax siRNA inhibited resveratrol-induced apoptosis. Resveratrol enhanced the apoptosis-inducing potential of TRAIL, and these effects were inhibited by either dominant negative FADD or caspase-8 siRNA. The combination of resveratrol and TRAIL enhanced the mitochondrial dysfunctions during apoptosis. These properties of resveratrol strongly suggest that it could be used either alone or in combination with TRAIL for the prevention and/or treatment of prostate cancer (Shankar et al., 2007).
Breast Cancer
Scarlatti et al. (2008) demonstrate that resveratrol acts via multiple pathways to trigger cell death, induces caspase-dependent and caspase-independent cell death in MCF-7 casp-3 cells, induces only caspase-independent cell death in MCF-7vc cells, and stimulates macroautophagy. Using BECN1 and hVPS34 (human vacuolar protein sorting 34) small interfering RNAs, they demonstrated that resveratrol activates Beclin 1-independent autophagy in both cell lines, whereas cell death via this uncommon form of autophagy occurs only in MCF-7vc cells. They also show that this variant form of autophagic cell death is blocked by the expression of caspase-3, but not by its enzymatic activity. In conclusion, this study reveals that non-canonical autophagy induced by resveratrol can act as a caspase-independent cell death mechanism in breast cancer cell.
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