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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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NEOPLASIA

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

Luca Paoluzzi1, Mithat Gonen2, Govind Bhagat3,4, Richard R. Furman5, Jeffrey R. Gardner6, Luigi Scotto1, Volodia D. Gueorguiev7, Mark L. Heaney6, Katia Manova7, and Owen A. O'Connor1,4

1 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; 2 Department of Epidemiology & Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; 3 Department of Pathology, Columbia University, New York, NY; 4 College of Physicians and Surgeons, The New York Presbyterian Hospital, Columbia University, New York, NY; 5 Division of Hematology/Oncology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY; and 6 Department of Medicine and 7 Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY

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 concentration-dependent 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.


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