Differential Effects of Quercetin and Two of Its Derivatives, Isorhamnetin and Isorhamnetin-3-glucuronide, in Inhibiting the Proliferation of Human Breast-Cancer MCF-7 Cells.

Quercetin (Que) has consistently been reported to be useful cytotoxic compound in vivo and in vitro, but little is known on its metabolites. Here, we examined and compared the cytotoxic effects of Que and its water-soluble metabolites, isorhamnetin (IS) and isorhamnetin-3-glucuronide (I3G), in human breast-cancer MCF-7 cells to uncover their tumor-inhibitory mechanisms and structure-function relationships. The results showed that Que, IS, and I3G could dose-dependently inhibit the growth of MCF-7 cells, and the cytotoxic effect was ranked as Que > IS > I3G. Furthermore, Que, IS, and I3G mediated cell-cycle arrest principally in S phase, followed by a decrease in the number of cells in G0/G1 and G2/M; moreover, 70.8, 68.9, and 49.8% of MCF-7 tumor cells entered early-phase apoptosis when treated with 100 μM Que, IS, and I3G for 48 h, respectively. Moreover, induction of apoptosis by Que, IS, and I3G was accompanied by the marginal generation of intracellular reactive oxygen species (ROS). Given these results, Que, IS, and I3G possess strong cytotoxic effects through an ROS-dependent apoptosis pathway in MCF-7 cells.