Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells
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- Lisa S. Chen
- Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston;
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- Sanjeev Redkar
- SuperGen Inc, Dublin, CA; and
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- David Bearss
- SuperGen Inc, Dublin, CA; and
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- William G. Wierda
- Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston
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- Varsha Gandhi
- Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston;
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説明
<jats:title>Abstract</jats:title><jats:p>Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compounds, SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-XL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction.</jats:p>
収録刊行物
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- Blood
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Blood 114 (19), 4150-4157, 2009-11-05
American Society of Hematology