Antiproliferative activity and apoptosis induction by 3′,4′-dibenzyloxyflavonol on human leukemia cells

Abstract

In this study, we investigated the effects of synthetic 3',4'-dibenzyloxyflavonol on viabilities of eight human tumor cells. It was cytotoxic against leukemia cells (HL-60, U-937, MOLT-3, K-562, NALM-6, Raji), with significant effects against P-glycoprotein-overexpressing K-562/ADR and Bcl-2-overexpressing U-937/ Bcl-2 cells, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. The IC50 value for the leukemia HL-60 cells was 0.8 +/- 0.1 mu M. This indicates a 60-fold greater toxicity than the naturally occurring flavonol quercetin. Synthetic 3',4'-dibenzyloxyflavonol induced S phase cell cycle arrest and was a potent apoptotic inducer in human leukemia cells. Cell death was (i) mediated by the activation and the cleavage of initiator and executioner caspases; (ii) prevented by the pan-caspase inhibitor z-VAD-fmk; (iii) associated with the release of cytochrome c and with the phosphorylation of members of the mitogen activated protein kinases including p38(MAPK), JNK/SAPK and ERK, and (iv) independent of the generation of reactive oxygen species. The synthetic 3',4'-dibenzyloxyflavonol is a potent cytotoxic compound against several human leukemia cells and might be useful in the development of new strategies in the fight against cancer.