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Giménez‐Bastida, Juan Antonio; Ávila‐Gálvez, María Ángeles; Espín, Juan Carlos; González‐Sarrías, Antonio
Molecular nutrition & food research, November 2019, 2019-11-00, 20191101, Volume: 63, Issue: 22Journal Article
Scope 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. Methods and Results 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 G2M/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. Conclusions 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. Physiologically relevant resveratrol (RSV) metabolites, as found in malignant tissues from breast cancer (BC) patients, induce cellular senescence in BC cells but not in non‐tumorigenic cells. Senescence is induced through the p53/p21 and p16/Rb pathways, depending on the RSV‐metabolite, and requires ABC transporters but not estrogen receptors. This mechanism might be involved in BC chemoprevention upon consumption of RSV‐containing foods. .
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