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The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo

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Abstract

Purpose

This study was designed to test the ability of the Bcl-2 family inhibitor ABT-263 to potentiate commonly used chemotherapeutic agents and regimens in hematologic tumor models.

Methods

Models of B-cell lymphoma and multiple myeloma were tested in vitro and in vivo with ABT-263 in combination with standard chemotherapeutic regimens, including VAP, CHOP and R-CHOP, as well as single cytotoxic agents including etoposide, rituximab, bortezomib and cyclophosphamide. Alterations in Bcl-2 family member expression patterns were analyzed to define mechanisms of potentiation.

Results

ABT-263 was additive with etoposide, vincristine and VAP in vitro in the diffuse large B-cell lymphoma line (DLBCL) DoHH-2, while rituximab potentiated its activity in SuDHL-4. Bortezomib strongly synergized with ABT-263 in the mantle cell lymphoma line Granta 519. Treatment of DoHH-2 with etoposide was associated with an increase in Puma expression, while bortezomib upregulated Noxa expression in Granta 519. Combination of ABT-263 with cytotoxic agents demonstrated superior tumor growth inhibition and delay in multiple models versus cytotoxic therapy alone, along with significant improvements in tumor response rates.

Conclusions

Inhibition of the Bcl-2 family of proteins by ABT-263 enhances the cytotoxicity of multiple chemotherapeutics in hematologic tumors and represents a promising addition to the therapeutic arsenal for treatment of these diseases.

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Authors and Affiliations

  1. Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA

    Scott Ackler, Michael J. Mitten, Kelly Foster, Anatol Oleksijew, Marion Refici, Stephen K. Tahir, Yu Xiao, Christin Tse, David J. Frost, Saul H. Rosenberg, Steven W. Elmore & Alexander R. Shoemaker

  2. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA

    Stephen W. Fesik

  3. Building AP3/105, 100 Abbott Park Road, Abbott Park, IL, 60064, USA

    Scott Ackler

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  1. Scott Ackler
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  2. Michael J. Mitten
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Correspondence to Scott Ackler.

Additional information

Scott Ackler and Michael J. Mitten contributed equally to this work.

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Ackler, S., Mitten, M.J., Foster, K. et al. The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemother Pharmacol 66, 869–880 (2010). https://doi.org/10.1007/s00280-009-1232-1

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  • DOI: https://doi.org/10.1007/s00280-009-1232-1

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