Conjugated Physiological Resveratrol Metabolites Induce Senescence in Breast Cancer Cells: Role of p53/p21 and p16/Rb Pathways, and ABC Transporters.

Recent evidence demonstrates that resveratrol (RSV) metabolites, but not free RSV, reach malignant tumors (MT) in breast cancer (BC) patients. Since these metabolites, as detected in MT, do not exert short-term antiproliferative or estrogenic/antiestrogenic activities, long-term tumor-senescent chemoprevention has been hypothesized. Consequently, here, for the first time, whether physiologically relevant RSV metabolites can induce senescence in BC cells is investigated. Human BC MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53), and non-tumorigenic MCF-10A cells are treated with free RSV and physiological-derived metabolites (RSV 3-O-glucuronide, RSV 3-O-sulfate, RSV 4'-O-sulfate, dihydroresveratrol (DH-RSV), and DH-RSV 3-Oglucuronide). Cellular senescence is measured by SA-β-gal activity and senescence-associated markers (p53, p21Cip1/Waf1 , p16INK4a , and phosphorylation status of retinoblastoma (pRb/tRb)). Although no effect is observed in MDA-MB-231 and normal cells, RSV metabolites induce cellular senescence in MCF-7 cells by reducing their clonogenic capacity and arresting cell cycle at G2 M/S phase, but do not induce apoptosis. Senescence is induced through the p53/p21Cip1/Waf1 and p16INK4a /Rb pathways, depending on the RSV metabolite, and requires ABC transporters, but not estrogen receptors. These data suggest that RSV metabolites, as found in MT from BC patients, are not de-conjugated to release free RSV, but enter the cells and may exert long-term tumor-senescent chemoprevention.