The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3, 4′, 5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and anti-oxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anti-cancer effects to support its potential as an anticancer agent in human populations.

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.

Cellular senescence is a state of permanent replicative arrest that is linked to telomere erosion and dysfunction that engages at least two mechanisms, the p53 and the p16INK4a -pRB pathways (1, 2). In cancer cells, the presence of oncogenic mutations, chemotherapeutic drugs, and oxidative stress can cause an acutely inducible, telomere-independent, stress-responsive form of cellular senescence, termed premature senescence (PS) 2 (3, 4). PS is considered a physiologic mechanism of DNA damage response occurring in chemotherapy (5-7), and the senescence induction could be an effective in vivo mechanism to limit tumor progression by preventing cancer cell proliferation or by blocking the cells at risk of neoplastic transformation (8). However, the physiological consequences of prematurely induced senescent (PIS) cancer cells remain elusive. PIS cancer cells have been shown to promote the growth of neighboring cells, and they are intrinsically resistant to chemotherapeutic agents (5, 9, 10). Importantly, cells in prematurely senescent tumors are capable of escaping growth arrest and re-entering the cell cycle, leading to tumor relapse (5, 9, 11). As for the mechanism underlying escape from DNA damage-induced senescence, overexpression of the cyclin-dependent kinase Cdc2 has been found in clones that bypassed replicative arrest in human non-small cell H1299 carcinoma (5) and in MCF-7 breast cancer cells (9). It was recently shown that survivin is the immediate downstream effector of Cdc2/Cdk1 and that phosphorylated survivin is necessary for the escape of senescent cells (12). Moreover, Twist1, which is involved in the metastatic dissemination of cancer cells, was shown to override oncogeneinduced senescence by abrogating cell cycle inhibition by p21 and p16 (11, 13), leading to complete epithelial-mesenchymal transition and implicating a direct link between escape from senescence and the acquisition of invasive features by cancer (11, 13). These data collectively suggest that there exist mechanisms that foster survival of PIS cancer cells and promote escape of these cells from the senescent state, which are likely detrimental to the overall therapeutic efficacy of cancer treatment. Because the p53 gene is frequently inactivated in 50% of * This work was supported, in whole or in part, by National Institutes of Health Grants R01 ES015323 (to M. A.) and K01-AR048582 and R03 CA125855 (to A. L. K.). This work was also supported by an Irving Scholar Award and Skin Cancer Foundation grant (to A. L. K. 2 The abbreviations used are: PS, premature senescence; PIS, prematurely induced senescent; ATM, ataxia telangiectasia, mutated; ATR, ATM and Rad3-related; Bfl-1/A1, Bcl2-related protein A1; Chk1/2, checkpoint kinase 1/2; DOX, doxorubicin; DYRK, the dual specificity, tyrosine phosphorylation-regulated kinase; MBP, maltose-binding protein; mTOR, mammalian target of rapamycin; mTORC1, the rapamycin-sensitive mTOR complex

Resveratrol (RES) is a potent anti-cancer agent. We have previously reported that RES arrests the growth of invasive human A431 squamous cell carcinoma cells. In this study, we show that oral administration of RES to highly tumor-susceptible p53+/−/SKH-1 mice markedly delayed ultraviolet B (UVB)-induced skin tumorigenesis and reduced the malignant conversion of benign papillomas to SCCs. Tumor growth factor β2 (TGF-β2) was predominantly overexpressed in UVB-induced SCCs and its expression was diminished in RES-treated SCCs/skin. In addition to inhibition of TGF-β2 expression, RES increased the level of E-cadherin. This RES-mediated TGF-β2 downregulation led to the inhibition of both TGF-β2/Smad-dependent and -independent pathways and suppressed the invasiveness of A431 cells. Addition of TGF-β2, but not TGF-β1, rescued the RES-mediated downregulation of p-ERK1/2, p-Smad3, and α-SMA. The Akt substrate cAMP response-binding protein (pCREB) transcription factor is known to regulate TGF-β2 expression, and RES treatment decreased phosphorylation of Akt and pCREB. Expression of constitutively active Akt blocked RES inhibition of CREB and TGF-β2, and rescued RES inhibition of cellular invasiveness. Our data indicate that RES suppresses UVB-induced malignant tumor progression in p53+/−/SKH-1 mice and that RES-inhibited invasiveness of human A431 SCC cells appears to occur, in part, through the Akt-mediated downregulation of TGF-β2.