Combination of Pim kinase inhibitors and Bcl-2 antagonists in chronic lymphocytic leukemia cells

Abstract

The Pim proteins are Ser/Thr kinases over-expressed in several hematological malignancies such as chronic lymphocytic leukemia (CLL) and some solid cancers like prostate cancer. Several small molecules have been developed to inhibit these kinases. In prostate cancer cell lines, the Pim kinase inhibitor SMI-4a and the Bcl-2 antagonist ABT-737 resulted in synergistic cytotoxicity. Akin to prostate cancer cells, CLL lymphocytes over-express Pim and Bcl-2 proteins. It was hypothesized that similar cytotoxic interaction should be observed in CLL. This study evaluated the in vitro cytotoxic effect of three Pim kinase inhibitors (AZD1208, SGI-1776 and SMI-4a) combined with Bcl-2 antagonists (ABT-737 or ABT-199) in malignant CLL lymphocytes. Data indicated Pim kinase inhibitors in combination with ABT-737 or ABT-199 resulted mostly in additive cytotoxicity with a few synergistic responses; however, the extent of synergism was less robust than that observed previously in prostate cancer cell lines treated with SMI-4a and ABT-737.

Keywords::

• Pim kinase
• CLL
• ABT-199
• SMI-4a
• AZD1208
• SGI-1776

Acknowledgments

The authors are grateful to Yuling Chen and Min Fu for obtaining blood samples and to Susan Lerner and Susan Smith for providing information on patient characteristics and clinical laboratory observations. Assistance provided by Dr Song from Dr Andrew Kraft's laboratory and Dr Andrew Kraft is greatly appreciated. We thank Bryan Tutt from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editorial help in preparing this manuscript. V.G. and W.G.W. are members of the CLL Research Consortium. This work was supported in part by grant CLL PO1 CA81534 from the National Cancer Institute, Department of Health and Human Services. This research is supported by the NIH/NCI under award number P30CA016672 and used the media core.

Potential conflict of interest

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