Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine

摘要: Previous studies demonstrated that ataxia telangiectasia mutated– and Rad3-related (ATR) kinase its downstream target checkpoint 1 (Chk1) facilitate survival of cells treated with nucleoside analogs other replication inhibitors. Recent results also Chk1 is depleted when are heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects 17-AAG major metabolite, 17-aminogeldanamycin (17-AG), on levels cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines clinical isolates. Cytarabine, at concentrations as low 30 nM, caused activating phosphorylation Chk1, loss phosphatase Cdc25A, S-phase slowing. Conversely, treatment 100 300 nM for 24 hours depletion was accompanied by diminished cytarabine-induced accumulation, decreased Cdc25A degradation, enhanced cytotoxicity measured inhibition colony formation induction apoptosis. Additional small inhibitory RNA (siRNA) sensitized cytarabine, whereas disruption phosphatidylinositol 3-kinase (PI3k) signaling pathway, which blocked Hsp90 inhibition, did not. Collectively, these suggest might represent a means reversing checkpoint-mediated resistance AML.