Antitumor activity of resveratrol and its sulfated metabolites against human breast cancer cells

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a naturally occurring polyphenolic compound found in grapes, wine and medicinal plants with a variety of biological and pharmacological activities including pronounced anticancer properties. These effects are observed despite its extremely low bioavailability and rapid clearance from the circulation due to extensive sulfation and glucuronidation in the intestine and liver. In order to determine whether its metabolites demonstrate any cytotoxic properties, three major human sulfated conjugates of resveratrol were synthesized and their anticancer activity evaluated against three breast cancer cell lines (two hormone-dependent: MCF-7 and ZR-75-1; one hormone-independent: MDA-MB-231) and one immortalized breast epithelial cell line (MCF-10A). We found that, in contrast to resveratrol, all three sulfated metabolites were less potent against MCF-7, MDA-MB-231 and ZR-75-1 cells (trans-resveratrol 3-O-sulfate < trans-resveratrol 4′-O-sulfate < trans-resveratrol 3-O-4′-O- disulfate) indicating that any conjugation of the phenolic groups with sulfuric acid strongly affecting the cytotoxicity. Interestingly, all sulfated metabolites were reduced about 10-fold, but showed nearly equal cytotoxicity towards nonmalignant MCF-10A breast cells (IC_{50 s}: 202-228 μM). In summary, in contrast to resveratrol its sulfated metabolites showed poor cytotoxicity in human malignant and nonmalignant breast cancer cell lines. However, the in vitro activity of the metabolites may not necessarily reflect their in vivo function, given the fact that the ubiquitously existing human sulfatases could convert the metabolites back to resveratrol in humans.