The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine

Walsby, Elisabeth Jane ORCID: https://orcid.org/0000-0001-8523-5017, Lazenby, Michelle, Pepper, Christopher John and Burnett, Alan Kenneth 2011. The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine. Leukemia 25 (3) , pp. 411-419. 10.1038/leu.2010.290

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Abstract

SNS-032 (BMS-387032) is a selective cyclin-dependent kinase (CDK) inhibitor. In this study, we evaluated its effects on primary acute myeloid leukemia (AML) samples (n=87). In vitro exposure to SNS-032 for 48 h resulted in a mean LD50 of 139±203 nM; Cytarabine (Ara-C) was more than 35 times less potent in the same cohort. SNS-032-induced a dose-dependent increase in annexin V staining and caspase-3 activation. At the molecular level, SNS-032 induced a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and inhibited the expression of CDK2 and CDK9 and dephosphorylated CDK7. Furthermore, the combination of SNS-032 and Ara-C showed remarkable synergy that was associated with reduced mRNA levels of the antiapoptotic genes XIAP, BCL2 and MCL1. In conclusion, SNS-032 is effective as a single agent and in combination with Ara-C in primary AML blasts. Treatment with Ara-C alone significantly induced the transcription of the antiapoptotic genes BCL2 and XIAP. In contrast, the combination of SNS-032 and Ara-C suppressed the transcription of BCL2, XIAP and MCL1. Therefore, the combination of SNS-032 and Ara-C may increase the sensitivity of AML cells to the cytotoxic effects of Ara-C by inhibiting the transcription of antiapoptotic genes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	acute myeloid leukemia; cyclin-dependent kinases; therapy
Publisher:	Nature Publishing Group
ISSN:	0887-6924
Last Modified:	20 Oct 2022 07:55
URI:	https://orca.cardiff.ac.uk/id/eprint/26918

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