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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2906-2916.
Prepublished online as a Blood First Edition Paper on June 30, 2008; DOI 10.1182/blood-2007-12-130781.
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Submitted December 28, 2007
Accepted June 24, 2008
The BH3-only mimetic ABT-737 synergizes the anti-neoplastic activity of proteasome inhibitors in lymphoid malignancies
Luca Paoluzzi, Mithat Gonen, Govind Bhagat, Richard R Furman, Jeffrey R Gardner, Luigi Scotto, Volodia D Gueorguiev, Mark L Heaney, Katia Manova, and Owen A O'Connor*
Herbert Irving Comprehensive Cancer Center, Columbia University, New York
Department of Epidemiology & Biostatistics, Memorial Sloan-Kettering Cancer Center, New York
Department of Pathology, Columbia University, New York, NY, United States
Divisions of Hematology/Oncology and Pathology, Weill Medical College of Cornell University and New York Presbyterian Hospital,, New York, NY, United States
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York
Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York
College of Physicians and Surgeons, The New York Presbyterian Hospital, New York
* Corresponding author; email: oo2130{at}columbia.edu.
Over-expression of anti-apoptotic members of the Bcl-2 family is observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying the anti-apoptotic influence of these proteins can potentially overcome this resistance, and may compliment conventional chemotherapy. ABT-737 is a BH3 only mimetic and potent inhibitor of the anti-apoptotic Bcl-2 family members Bcl-2, Bcl- XL and Bcl-w. In vitro, ABT-737 exhibited concentration dependent cytotoxicity against a broad panel of lymphoma cell lines including mantle cell (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 proteasome inhibitor. 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 SCID beige mouse models of MCL, the addition of ABT-737 to bortezomib enhanced efficacy compared to either drug alone and to 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.
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