A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6 Journal Article
| Authors: | Baughn, L. B.; Di Liberto, M.; Wu, K.; Toogood, P. L.; Louie, T.; Gottschalk, R.; Niesvizky, R.; Cho, H.; Ely, S.; Moore, M. A. S.; Chen-Kiang, S. |
| Article Title: | A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6 |
| Abstract: | Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G 1 arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18INK4c. Inhibition of cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers. ©2006 American Association for Cancer Research. |
| Keywords: | controlled study; unclassified drug; human cell; drug potentiation; nonhuman; pyridines; animal cell; mouse; animals; mice; animal tissue; apoptosis; enzyme inhibition; multiple myeloma; bone marrow; animal experiment; animal model; dexamethasone; mice, scid; xenograft model antitumor assays; drug mechanism; xenograft; cell transformation; cell growth processes; cell cycle arrest; piperazines; tumor growth; mice, inbred nod; ex vivo study; cyclin dependent kinase inhibitor; cell cycle g1 phase; g1 phase; cyclin dependent kinase 4; cyclin dependent kinase inhibitor 2c; cyclin-dependent kinase 4; cyclin dependent kinase 6; cyclin-dependent kinase 6; myeloma cell; pd 0332991; cyclin-dependent kinase inhibitor p18 |
| Journal Title: | Cancer Research |
| Volume: | 66 |
| Issue: | 15 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-08-01 |
| Start Page: | 7661 |
| End Page: | 7667 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-06-1098 |
| PUBMED: | 16885367 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 47" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus" |
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