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Blood, 7 May 2009, Vol. 113, No. 19, pp. 4637-4645. Prepublished online as a Blood First Edition Paper on February 20, 2009; DOI 10.1182/blood-2008-12-190256. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-12-190256v1 113/19/4637    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, R. Articles by Plunkett, W. Search for Related Content PubMed PubMed Citation Articles by Chen, R. Articles by Plunkett, W. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia Rong Chen1, William G. Wierda2, Sherri Chubb1, Rachael E. Hawtin3, Judith A. Fox3, Michael J. Keating2, Varsha Gandhi1,2, and William Plunkett1,2 Departments of 1 Experimental Therapeutics and 2 Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston; and 3 Sunesis Pharmaceuticals, South San Francisco, CA Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in chronic lymphocytic leukemia cells by inhibiting Cdk7 and Cdk9, which control transcription. Here we studied the novel Cdk inhibitor SNS-032, which exhibits potent and selective inhibitory activity against Cdk2, Cdk7, and Cdk9. We hypothesized that transient inhibition of transcription by SNS-032 would decrease antiapoptotic proteins, resulting in cell death. SNS-032 effectively killed chronic lymphocytic leukemia cells in vitro regardless of prognostic indicators and treatment history. This was associated with inhibition of phosphorylation of RNA polymerase II and inhibition of RNA synthesis. Consistent with the intrinsic turnover rates of their transcripts and proteins, antiapoptotic proteins, such as Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), were rapidly reduced on exposure to SNS-032, whereas Bcl-2 protein was not affected. The initial decrease of Mcl-1 protein was the result of transcriptional inhibition rather than cleavage by caspase. Compared with flavopiridol and roscovitine, SNS-032 was more potent, both in inhibition of RNA synthesis and at induction of apoptosis. SNS-032 activity was readily reversible; removal of SNS-032 reactivated RNA polymerase II, which led to resynthesis of Mcl-1 and cell survival. Thus, these data support the clinical development of SNS-032 in diseases that require short-lived oncoproteins for survival. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. G. Holtan, D. J. Creedon, P. Haluska, and S. N. Markovic Cancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents Mayo Clin. Proc., November 1, 2009; 84(11): 985 - 1000. [Abstract] [Full Text] [PDF]

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