[PDF][PDF] Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia

M Konopleva, R Contractor, T Tsao, I Samudio… - Cancer cell, 2006 - cell.com
M Konopleva, R Contractor, T Tsao, I Samudio, PP Ruvolo, S Kitada, X Deng, D Zhai, YX Shi…
Cancer cell, 2006cell.com
BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737
is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and
small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills
acute myeloid leukemia blast, progenitor, and stem cells without affecting normal
hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-
dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with …
Summary
BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.
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