Quercetin arrests G2/M phase and induces caspase-dependent cell death in U937 cells.

Quercetin, a natural product derived from grapes, has been shown to prevent carcinogenesis in murine models. We report here that quercetin induces anti-proliferation and arrests G2/M phase in U937 cells. The G2/M phase accumulation was accompanied by an increase in the level of the cyclin B. In contrast, the level of the cyclin D, cyclin E, E2F1, and E2F2 was marked decreased in quercetin-treated U937 cells. Removal of quercetin from the culture medium stimulates U937 cells to synchronously re-enter the cell cycle, decrease expression level of cyclin B, and increased the expression level of cyclin D and cyclin E. These data demonstrate that quercetin causes reversible G2/M phase arrest, which was related with dramatic changes in the level of cyclin B, cyclin D, and cyclin E. Quercetin-induced down-regulation of cyclin D and cyclin E was associated with suppression of transcriptional levels but not protein stability. In addition, quercetin-treated U937 cells showed DNA fragmentation, increased sub-G1 population, and generated a 60kDa cleavage product of PLC-gamma1 in a dose-dependent manner, which were significantly inhibited by z-VAD-fmk. These data clearly indicate that quercetin-induced apoptosis is associated with caspase activation. In summary, the growth inhibition of the quercetin is highly related to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis in human promonocytic U937 cells.