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- Title
Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma.
- Authors
Raje, N.; Hideshima, T.; Mukherjee, S.; Raab, M.; Vallet, S.; Chhetri, S.; Cirstea, D.; Pozzi, S.; Mitsiades, C.; Rooney, M.; Kiziltepe, T.; Podar, K.; Okawa, Y.; Ikeda, H.; Carrasco, R.; Richardson, P. G.; Chauhan, D.; Munshi, N. C.; Sharma, S.; Parikh, H.
- Abstract
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
- Subjects
CYCLIN-dependent kinases; MULTIPLE myeloma; PLASMA cells; CELL cycle regulation; DRUG synergism; APOPTOSIS; PHYSICAL therapy
- Publication
Leukemia (08876924), 2009, Vol 23, Issue 5, p961
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2008.378