Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs.
When human leukemia HL-60 cells were treated with 10(-7) M bufalin, the amounts of both topoisomerase (topo) II alpha and II beta and the activity of topo II decreased markedly and were almost undetectable 18 h after the start of treatment. The level of topo II mRNA started to decrease immediately after the start of treatment with bufalin, with a subsequent decrease in the amount of topo II alpha protein. These changes preceded the fragmentation of DNA, a typical feature of apoptosis. The 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 amount and activity of the enzyme and to the induction of apoptosis. A reduction 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 acid (RA) on HL-60 cells: pretreatment of HL-60 cells with 10(-7) M bufalin for 6 h increased the inhibitory effects of cisplatin and RA on cell growth and enhanced the induction of cell death.
Hashimoto
S
S
Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Jing
Y
Y
Kawazoe
N
N
Masuda
Y
Y
Nakajo
S
S
Yoshida
T
T
Kuroiwa
Y
Y
Nakaya
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D053938:DNA Fragmentation; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002018:Bufanolides; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D059005:Topoisomerase II Inhibitors; D014212:Tretinoin; D004250:DNA Topoisomerases, Type II; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin; C022777:bufalin