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

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.
Mesh Terms:
Animals, Apoptosis, Biphenyl Compounds, Cell Line, Dimerization, Drug Resistance, Neoplasm, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Nitrophenols, Piperazines, Protein Conformation, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, Recombinant Fusion Proteins, Sulfonamides, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Cancer Cell
Date: Nov. 01, 2006
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