Abstract
The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-x(L), and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-x(L) predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-x(L) or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-x(L)/Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / pharmacology*
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Aniline Compounds / therapeutic use
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Animals
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Apoptosis Regulatory Proteins / antagonists & inhibitors*
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Biphenyl Compounds / pharmacology*
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Biphenyl Compounds / therapeutic use
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Cell Death / drug effects
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Cytoprotection / drug effects
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Drug Resistance, Neoplasm / drug effects
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Etoposide / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Leukemia / drug therapy*
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Leukemia / genetics
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Leukemia / pathology
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Lymphoma / drug therapy*
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Lymphoma / genetics
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Lymphoma / pathology
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Membrane Proteins / metabolism
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Mice
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Molecular Targeted Therapy*
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Mutant Proteins / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / pharmacology*
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Nitrophenols / therapeutic use
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Piperazines / pharmacology
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Piperazines / therapeutic use
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Protein Binding / drug effects
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / antagonists & inhibitors*
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bcl-X Protein / metabolism
Substances
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ABT-737
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Aniline Compounds
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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BCL2L2 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Biphenyl Compounds
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Membrane Proteins
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Mutant Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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bcl-X Protein
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Etoposide
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navitoclax