Chemoprevention involving the use of natural or synthetic agents to suppress, block or reverse the process of carcinogenesis could be an effective approach to reduce the incidence of prostate cancer. Indeed, prostate cancer represents an excellent candidate disease for chemoprevention, because it is typically diagnosed in elderly men. Even a modest delay in the neoplastic development achieved through pharmacological or therapeutic intervention could result in substantial reduction in the incidence of the clinically detectable disease. Consistent with this assumption, there is intense activity in defining chemopreventive agents and molecular targets for prostate cancer chemoprevention. Among the many such agents that are available, for a variety of reasons, naturally occurring nontoxic dietary substances are preferred.
Of this class of compounds, epigallocatechin gallate (EGCg) from tea and resveratrol from red grapes, which are two of the most widely studied polyphenols, have gained recognition as important chemopreventive agents and as modulators of tumor cell response to chemotherapy. In vitro and in vivo studies have demonstrated that EGCg and resveratrol can affect a wide array of signaling and molecular pathways, resulting in cancer cell growth inhibition, apoptosis and inhibition of invasion, angiogenesis and metastasis. In prostate cancer, EGCg and resveratrol alter numerous intracellular pathways, including inhibition of the ERK- and Akt-mediated signal transduction pathways, inhibition of PMA-dependent PKC activation, block of cell cycle progression, induction of apoptotic events such as activation of caspases, and alteration of Bcl-2 family members ratio. Animal models, that include xenograft tumor models as well as transgenic animal studies, have demonstrated that green tea or wine polyphenols can decrease the tumorigenic potential of prostate cancer.
Green tea, derived from the plant Camellia sinensis, is a popular beverage in some parts of the world. Studies conducted on cell-culture systems and animal models as well as human epidemiological studies show that the polyphenols that are present in green tea could afford protection against a variety of cancer types including prostate cancer. The major polyphenolic constituent of green tea is epigallocatechin-3-gallate or EGCG. Clinical studies have shown the usefulness of green tea polyphenols on prostate cancer chemoprevention.
Resveratrol (3,4′,5-trihydroxy-trans- stilbene) is a polyphenolic phytoalexin notably present in red grapes skins but also in many other plants and fruits, including blueberries, mulberries. It is believed to be responsible for the so-called ‘French paradox’, in which consumption of red wine has been shown to reduce the mortality rates from cardiovascular diseases. During the last decade resveratrol has been shown to possess a compelling wide array of pharmacologic properties. Resveratrol affects all three stages of carcinogenesis (initiation, promotion, and progression) by altering signal transduction pathways that control cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis, and hence is considered by some to be a promisng anticancer therapy. In 1997, resveratrol was the first common constituent of human diet to demonstrate chemopreventive activity in animal models of cancer. Clinical trials to investigate the effects of resveratrol in cancer are currently ongoing.
SphK1/S1P signaling is a molecular target of polyphenols
We have shown that epigallocatechin gallate (EGCg), resveratrol or a mixture of polyphenols from green tea (Polyphenon E, PPE) or grapevine extract (vineatrol) can block prostate cancer cell growth in vitro and in vivo, an event associated with SphK1 inhibition. Our results establish that SphK1 is a downstream effector of the ERK/Phospholipase D (PLD) signaling cascade, which is inhibited by green tea and wine polyphenols. Enforced expression of SphK1 significantly impaired the ability of green tea and wine polyphenols to induce apoptosis in PC-3 and C4-2B prostate cancer cells. SphK1 overexpression also blocked the cytotoxic effects of pharmacological inhibitors of PLD and ERK activities.
The therapeutic efficacy of green tea and wine polyphenols on tumor growth and SphK1 signaling were confirmed using an heterotopic PC-3 tumor in place model established in nude mice. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to treatment with polyphenols. Furthermore, using an orthotopic PC-3/green fluorescent protein model, the chemopreventive effect of EGCg or PPE diet was associated with a significant SphK1 inhibition, pronounced decrease in primary tumor volume, and occurrence and number of metastases. These results provide the first demonstration that the prosurvival, anti-apoptotic SphK1/S1P pathway represents a common target of dietary green tea and wine polyphenols in cancer.