期刊
LEUKEMIA
卷 23, 期 5, 页码 961-970出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2008.378
关键词
cyclin D; cyclin-dependent kinase; multiple myeloma; P276-00; small molecule
资金
- Multiple Myeloma Research Foundation Awards
- ASCO Career Development Award
- Department of Veterans Affairs merit review
- Leukemia and Lymphoma Society Scholar in Translational Research Award (NCM)
- NIH [P50-100707, PO1-78378, RO1-50947]
Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM. Leukemia (2009) 23, 961-970; doi:10.1038/leu.2008.378; published online 8 January 2009
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