title: The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine.
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 LD(50) 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.
authors.affiliation: Cardiff Experimental Cancer Medicine Centre, Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff, UK. walsbyej@cf.ac.uk
authors.forename: E
authors.initials: E
authors.lastname: Walsby
authors.forename: M
authors.initials: M
authors.lastname: Lazenby
authors.forename: C
authors.initials: C
authors.lastname: Pepper
authors.forename: A K
authors.initials: AK
authors.lastname: Burnett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003561:Cytarabine / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000494:pharmacology*; D010766:Phosphorylation; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D013844:Thiazoles; D003561:Cytarabine; D018844:Cyclin-Dependent Kinases