BUFALIN REDUCES THE LEVEL OF TOPOISOMERASE-II IN HUMAN LEUKEMIA-CELLSAND AFFECTS THE CYTOTOXICITY OF ANTICANCER DRUGS

When human leukemia HL-60 cells were treated with 10(-7) M bufalin, th e amounts of both topoisomerase (topo) II alpha and II beta and the ac tivity of topo II decreased markedly and were almost undetectable 18h after the start of treatment. The level of topo II mRNA started to dec rease immediately after the start of treatment with bufalin, with a su bsequent decrease in the amount of topo II alpha protein. These change s preceded the fragmentation of DNA, a typical feature of apoptosis. T he results suggest that bufalin caused a marked decrease in the steady -state level of topo II alpha mRNA, which led to a decrease in the amo unt and activity of the enzyme and to the induction of apoptosis. A re duction in the level of topo II alpha by bufalin was also observed in other lines of human leukemia cells such as ML1 and U937. The results were exploited to potentiate the effects of cisplatin and retinoic aci d (RA) on HL-60 cells: pretreatment of HL-60 cells with 10(-7) M bufal in for 6 h increased the inhibitory effects of cisplatin and RA on cel l growth and enhanced the induction of cell death. (C) 1997 Elsevier S cience Ltd.