Author: Merino, Delphine; Khaw, Seong L.; Glaser, Stefan P.; Anderson, Daniel J.; Belmont, Lisa D.; Wong, Chihunt; Yue, Peng; Robati, Mikara; Phipson, Belinda; Fairlie, Walter D.; Lee, Erinna F.; Campbell, Kirsteen J.; Vandenberg, Cassandra J.; Cory, Suzanne; Roberts, Andrew W.; Ludlam, Mary J. C.; Huang, David C. S.; Bouillet, Philippe
Description: 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.
Subject headings: Aniline Compounds; Animals; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Biphenyl Compounds; Cell Death; Cytoprotection; Drug Resistance; Neoplasm; Etoposide; Gene Expression Regulation; Neoplastic; Humans; Leukemia; Lymphoma; Membrane Proteins; Mice; Molecular Targeted Therapy; Mutant Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; bcl-X Protein
Publication year: 2012
Journal or book title: Blood
Volume: 119
Issue: 24
Pages: 5807-5816
Find the full text: https://www.strategian.com/fulltext/Merino2012.pdf
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Serial number: 4018