Document Detail


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.
MedLine Citation:
PMID:  16885367     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 p18(INK4c). 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.
Authors:
Linda B Baughn; Maurizio Di Liberto; Kaida Wu; Peter L Toogood; Tracey Louie; Rachel Gottschalk; Ruben Niesvizky; Hearn Cho; Scott Ely; Malcolm A S Moore; Selina Chen-Kiang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-03     Completed Date:  2006-09-28     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7661-7     Citation Subset:  IM    
Affiliation:
Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Growth Processes / drug effects
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cyclin-Dependent Kinase Inhibitor p18 / metabolism
Dexamethasone / pharmacology
G1 Phase / drug effects
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Multiple Myeloma / drug therapy*,  enzymology,  pathology
Piperazines / pharmacology*
Pyridines / pharmacology*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
R01 AR 49436/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-ylpyridin-2-ylamino)-8H-pyrido(2,3-d)pyrimidin-7-one; 0/Cyclin-Dependent Kinase Inhibitor p18; 0/Piperazines; 0/Pyridines; 50-02-2/Dexamethasone; EC 2.7.11.22/Cyclin-Dependent Kinase 4; EC 2.7.11.22/Cyclin-Dependent Kinase 6

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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