Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

N. Raje*, T. Hideshima, S. Mukherjee, M. Raab, S. Vallet, S. Chhetri, D. Cirstea, S. Pozzi, C. Mitsiades, M. Rooney, T. Kiziltepe, K. Podar, Y. Okawa, H. Ikeda, R. Carrasco, P. G. Richardson, D. Chauhan, N. C. Munshi, S. Sharma, H. ParikhB. Chabner, D. Scadden, K. C. Anderson

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

62 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)961-970
Number of pages10
JournalLeukemia
Volume23
Issue number5
DOIs
Publication statusPublished - May 2009
Externally publishedYes

Keywords

  • Oligonucleotide Array Sequence Analysis
  • Humans
  • Antineoplastic Agents/therapeutic use
  • Drug Resistance, Neoplasm
  • Male
  • Transplantation, Heterologous
  • Gene Expression Profiling
  • Stromal Cells/drug effects
  • Cell Cycle/drug effects
  • Insulin-Like Growth Factor I/metabolism
  • Flavones/therapeutic use
  • Boronic Acids/therapeutic use
  • Cell Proliferation/drug effects
  • Pyrazines/therapeutic use
  • Tumor Cells, Cultured
  • Drug Evaluation, Preclinical
  • Multiple Myeloma/drug therapy
  • Bone Marrow/drug effects
  • Bortezomib
  • Cell Adhesion/drug effects
  • Down-Regulation
  • Apoptosis/drug effects
  • Mice, SCID
  • Blotting, Western
  • Caspases/metabolism
  • Drug Synergism
  • Animals
  • Interleukin-6/metabolism
  • Cyclin D1/antagonists & inhibitors
  • Mice
  • Retinoblastoma Protein/metabolism
  • Cyclin-Dependent Kinase Inhibitor Proteins/antagonists & inhibitors
  • Phosphorylation/drug effects

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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