MECHANISM OF INDUCTION OF DIFFRENTIATION INLEUKEMIA CELLS BY TOPOISOMERASE INHIBITORS

喜树碱和VP16分别是拓扑异构酶I和拓扑异构酶II的抑制剂。我们之前已经发现这些拓扑异构酶抑制剂和蟾毒灵（中药禅素的有效成分）可以诱导多种人类白血病细胞系的分化。本研究旨在探讨这些分化诱导剂诱导人白血病细胞分化的机制。蟾毒灵通过信号转导途径间接抑制白血病HL60细胞拓扑异构酶II。因此，蟾毒灵被归类为拓扑异构酶II的运动抑制剂。所有这些拓扑异构酶抑制剂都将白血病细胞的细胞周期阻滞在G2/M期。蟾毒灵与喜树碱或VP16联用对白血病细胞的诱导分化有协同作用。临床上用于治疗急性早幼粒细胞白血病的维甲酸与喜树碱或VP16联合使用对白血病细胞的分化也有明显的协同作用。虽然喜树碱和VP16是已知的凋亡诱导剂，但我们发现蟾毒灵在使用浓度高于诱导分化时也能诱导HL60细胞凋亡。喜树碱与VP16、视黄酸与VP16或蟾毒灵与视黄酸联合治疗对诱导凋亡有协同作用。这些结果表明这些拓扑异构酶抑制剂在癌症分化-细胞凋亡诱导治疗中的有用性。

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.