The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies Journal Article

Authors: Paoluzzi, L.; Gonen, M.; Bhagat, G.; Furman, R. R.; Gardner, J. R.; Scotto, L.; Gueorguiev, V. D.; Heaney, M. L.; Manova, K.; O'Connor, O. A.
Article Title: The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies
Abstract: Overexpression of antiapoptotic members of the Bcl-2 family is observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying the antiapoptotic influence of these proteins can potentially overcome this resistance, and may complement conventional chemotherapy. ABT-737 is a BH3-only mimetic and potent inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-XL, and Bcl-w. In vitro, ABT-737 exhibited concentrationdependent cytotoxicity against a broad panel of lymphoma cell lines including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). ABT-737 showed synergism when combined with the proteasome inhibitors bortezomib or carfilzomib in select lymphoma cell lines and induced potent mitochondrial membrane depolarization and apoptosis when combined with either. ABT-737 plus bortezomib also induced significant apoptosis in primary samples of MCL, DLBCL, and chronic lymphocytic leukemia (CLL) but no significant cytotoxic effect was observed in peripheral blood mononuclear cells from healthy donors. In severe combined immunodeficient beige mouse models of MCL, the addition of ABT-737 to bortezomib enhanced efficacy compared with either drug alone and with the control. Collectively, these data suggest that ABT-737 alone or in combination with a proteasome inhibitor represents a novel and potentially important platform for the treatment of B-cell malignancies. © 2008 by The American Society of Hematology.
Keywords: controlled study; unclassified drug; human cell; dose response; drug efficacy; drug potentiation; nonhuman; antineoplastic agents; antineoplastic agent; animal cell; mouse; animal; metabolism; animals; mice; cell death; drug inhibition; protein bcl 2; apoptosis; bortezomib; proteasome; proteasome inhibitor; mantle cell lymphoma; boronic acids; proteasome endopeptidase complex; pyrazines; confocal microscopy; microscopy, confocal; animal experiment; animal model; mitochondrial membrane potential; in vivo study; cytotoxicity; drug effect; drug resistance; drug screening; enzymology; pathology; dose-response relationship, drug; drug resistance, neoplasm; xenograft model antitumor assays; enzyme inhibitor; protein bcl xl; cell line, tumor; drug synergism; b cell lymphoma; drug antagonism; donor; tissue donors; mononuclear cell; leukocytes, mononuclear; peripheral blood stem cell; enzyme inhibitors; sulfonamide; sulfonamides; protein bcl w; tumor cell line; lymphoma; health; large cell lymphoma; lymphoma, large b-cell, diffuse; piperazines; immune deficiency; piperazine derivative; chronic lymphatic leukemia; cell level; mitochondrial membrane; proto-oncogene proteins c-bcl-2; boronic acid derivative; pyrazine derivative; membrane potential, mitochondrial; leukemia, lymphocytic, chronic, b-cell; lymphoma, mantle-cell; carfilzomib; 4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide; b cell leukemia; nitrophenols; bh3 protein; molecular mimicry; membrane depolarization; abt-737; biphenyl derivative; nitrophenol; biphenyl compounds
Journal Title: Blood
Volume: 112
Issue: 7
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2008-10-01
Start Page: 2906
End Page: 2916
Language: English
DOI: 10.1182/blood-2007-12-130781
PUBMED: 18591385
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 43" - "Export Date: 17 November 2011" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Mark L Heaney
    89 Heaney
  2. Mithat Gonen
    701 Gonen
  3. Jeffrey Gardner
    33 Gardner