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Research Articles: Therapeutics, Targets, and Development

Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions

Departments of ¹ Medicine and ² Biochemistry, Virginia Commonwealth University, Richmond, Virginia and ³ Department of Biochemistry and Biological Sciences, National University of San Luis, San Luis, Argentina

Requests for reprints: Steven Grant, Massey Cancer Center, Virginia Commonwealth University, Medical College of Virginia Campus, MCV Station Box 980035, Richmond, VA 23298. Phone: 804-828-5211; Fax: 804-225-3788. E-mail: stgrant{at}hsc.vcu.edu

Abstract

The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the histone deacetylase inhibitor vorinostat and the cyclin-dependent kinase inhibitor flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/flavopiridol was associated with enhanced inhibition of phosphorylation of RNA polymerase II and was amplified by caspase-mediated protein degradation. Chromatin immunoprecipitation analysis revealed that XIAP and Mcl-1 down-regulation were also accompanied by both decreased association of nuclear factor-B (XIAP) and increased E2F1 association (Mcl-1) with their promoter regions, respectively. Ectopic expression of Mcl-1 but not XIAP partially protected cells from flavopiridol/vorinostat–mediated mitochondrial injury at 48 h, but both did not significantly restored clonogenic potential. Flavopiridol/vorinostat–mediated transcriptional repression of XIAP, Mcl-1–enhanced apoptosis, and loss of clonogenic potential also occurred in primary acute myelogenous leukemia (AML) blasts. Together, these findings indicate that transcriptional repression of XIAP and Mcl-1 by flavopiridol/vorinostat contributes functionally to apoptosis induction at early exposure intervals and raise the possibility that expression levels may be a useful surrogate marker for activity in current trials. [Mol Cancer Ther 2007;6(2):692–702]

Grant support: National Cancer Institute grants CA63753, CA93738, and CA100866; Leukemia and Lymphoma Society of America grant R6059-06; the V Foundation; and the Department of Defense.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/13/06; revised 11/ 7/06; accepted 12/19/06.

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