ATPase inhibitors suppress actinomycin D-induced apoptosis in leukemia cells.
BACKGROUND
Apoptosis is mediated by many kinds of enzymes such as caspases, DNase and protein kinases. Recently, ATPase has been shown to be involved in the apoptotic system, but its role is not fully understood.


METHODS
We investigated the effect of 8 species of ATPase inhibitors on actinomycin D plus colcemid-induced apoptosis in human megakaryoblastic leukemia CMK-7 cells by monitoring caspase-3 activation and DNA cleavage.


RESULTS
2,3-Butanedione monoxime (BDM), lansoprazole, cyclopiazonic acid, geldanamycin and radicicol suppressed the apoptosis. Among these compounds, geldanamycin was the strongest suppressor of both caspase-3 activation and DNA cleavage. Furthermore, Western blotting showed that radicicol suppressed the proteolytic cleavage of procaspase-9 more strongly than BDM, lansoprazole or cyclopiazonic acid.


CONCLUSIONS
Since geldanamycin and radicicol are specific inhibitors of the ATPase in HSP90, the present result implies that ATPase activity in HSP90 plays some role in this apoptosis.
Shiono
Yoshihito
Y
Research Institute of Biological Resources, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan.
Fujita
Yasuko
Y
Oka
Syuichi
S
Yamazaki
Yoshimitsu
Y
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003609:Dactinomycin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003703:Demecolcine / Q000494:pharmacology; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D064747:Lansoprazole; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D064747:Lansoprazole; C004717:diacetylmonoxime; D003609:Dactinomycin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000251:Adenosine Triphosphatases; D003931:Diacetyl; D009853:Omeprazole; C000543:cyclopiazonic acid; D003703:Demecolcine