Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms

Abstract

Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3, 4', 5-trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ ATR; transcription factors NF-κB, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl-2 and Bcl-X L . In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the anti-proliferative mechanisms of resveratrol.

Resveratrol Exerts Differential Effects in Vitro and in Vivo against Ovarian Cancer Cells

“…Review of the recent literature provides a convincing body of evidence demonstrating resveratrol to have numerous antitumor properties including the ability to decrease cell proliferation, induce apoptosis, and inhibit angiogenesis and tumor growth by mediating a variety of cellular pathways (Bishayee, 2009;Athar et al, 2009;Weng & Yen, 2012). These effects have been documented in numerous types of cancer cells from skin, breast, ovary, prostate, gastrointestinal tract and lung (Aggarwal et al, 2004;Kundu & Surh, 2008).…”

“…Although NuTu-19 ovarian cancer cells were shown to be apoptosis resistant, these cells can be induced to undergo apoptosis when tumor-associated cellular mechanisms are stabilized (Feki et al, 2005;Brard et al, 2006). Since resveratrol mediates effects on a range of pathways (Athar et al, 2009;Bishayee, 2009;Weng & Yen, 2012), cellular stabilization and apoptosis was expected. However, regions of ovarian cancer from control and resveratrol-treated animals showed no detectable difference in fluorescence compared to the negative controls, indicating the absence of resveratrol-mediated apoptosis in the NuTu-19 cells in an in vivo condition.…”

“…Cell proliferation and DNA synthesis is decreased through its inhibitory actions on ribonucleotide reductase, DNA polymerase, and ornithine decarboxylase activities as well as by cell cycle arrest at the G2-S checkpoint. Apoptosis is induced in various malignant cells by resveratrol through up-regulation of CD95L expression, caspase activation, stabilization of p53, and inhibition of nuclear factor κB activity (Athar et al, 2009;Delmas et al, 2011;Shukla and Singh, 2011). Several pathways are intertwined and influence additional mechanisms involved in cellular invasion and metastasis, such as the regulation of growth factors and matrix metalloproteins (Weng & Yen, 2012).…”

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“…It is induced in many types of cells by inflammatory mediators and various stimuli (e.g., oncogenes, mitogens, tumor promoters, and growth factors). COX-2-dependent reactions can generate ROS during the conversion of arachidonic acid to prostaglandin G2, causing direct oxidative damage to DNA [63]. Moreover, the products prostaglandins are thought to be a causative factor of cellular injury and may ultimately result in carcinogenesis.…”

Modulation of Nrf2/Keap1 pathway by dietary phytochemicals

“…60 Several mechanisms may account for the cancer preventive effect of resveratrol including inhibition of free radical formation and activities of cyclooxygenase (COX), hydroperoxidase, inducible nitric oxide synthase, cytochrome P-450 and protein kinase C, regulation of growth factors and matrix metalloproteins. 61 These multiple mechanisms participate to the comprehensive influence of resveratrol's effects against cancer cells. 62…”