Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells

摘要: DNA methylation and BLC-2 are potential therapeutic targets in acute myeloid leukemia (AML). We investigated pharmacologic interaction between the methyltransferase inhibitor 5-azacytidine (5-AZA) BCL-2 ABT-737. Increased expression determined by reverse phase protein analysis was associated with poor survival AML patients unfavorable cytogenetics (n = 195). found that 5-AZA, which itself has modest apoptotic activity, acts synergistically ABT-737 to induce apoptosis. The 5-AZA/ABT-737 combination enhanced mitochondrial outer membrane permeabilization, as evidenced effective conformational activation of BAX ∆ψm loss. Although absence p53 limited activities 5-AZA single agents, induced apoptosis independent expression. down-regulated MCL-1, known mediate resistance ABT-737, a p53-independent manner. cells seven eight patients. significantly reduced MCL-1 levels two three samples examined. Our data provide molecular rationale for this strategy therapy.