MECHANISM OF INDUCTION OF DIFFRENTIATION INLEUKEMIA CELLS BY TOPOISOMERASE INHIBITORS

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Camptothecin and VP16 are known as inhibitors for topoisomerase I and II, respectively. We have previously found that these topoisomerase inhibitors and bufalin, an active principle of the Chinese medicine chan'su, induce differentiation of various kinds of human leudemia cell lines. The present study was undertaken to investigate the mechanism og the induction of differintiation in human leukemia cells by these differentiationinducers. Bufalin indirectly inhibits topoisomerase II in leukemia HL60 cells via signal transduction pathway. Therefore, bufalin is classified as a movel inhibitor of topoisomerasa II.All these topoisomerase inhibitors arresred the cell cycle of leukemia cells at the G2/M phase. Synergistic effects on the induction of differentiation in leukemia cells were observed by combination of bufalin with camptothecin or VP16. Combination of retinoic acid, clinically used as a drug for acute promyelocytic leukemia, with camptothecin or VP16 also showed marked synergistic effects on the differentiation of leukemia cells. Although camptothecin and VP16 are known as inducers of apoptosis, we found that bufalin can also induce apoptosis in HL60 cells when used at higher concentrations than used for inducing differentiation. Synergistic effects on the induction of apoprosis were observed by combined teratment of camptothecin with VP16, retinoic acid with VP16, or bufalin with retinoic acid. These results suggest the usefulness of these topoisomerase ingibitors for diffentiation-apoptosis inducing therapy for cancer.