651. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.
- Author
-
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, and Andreeff M more...
- Subjects
- Animals, Cell Line, Dimerization, Hematopoietic Stem Cells physiology, Humans, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins metabolism, Piperazines metabolism, Piperazines therapeutic use, Protein Conformation, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2 chemistry, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, bcl-2 Homologous Antagonist-Killer Protein genetics, bcl-2 Homologous Antagonist-Killer Protein metabolism, bcl-2-Associated X Protein chemistry, bcl-2-Associated X Protein genetics, bcl-2-Associated X Protein metabolism, Apoptosis physiology, Biphenyl Compounds metabolism, Biphenyl Compounds therapeutic use, Drug Resistance, Neoplasm physiology, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Nitrophenols metabolism, Nitrophenols therapeutic use, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sulfonamides metabolism, Sulfonamides therapeutic use
- Abstract
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. more...
- Published
- 2006
- Full Text
- View/download PDF