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Blood, 1 August 2008, Vol. 112, No. 3, pp. 793-804. Prepublished online as a Blood First Edition Paper on May 27, 2008; DOI 10.1182/blood-2007-10-116376. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-10-116376v1 112/3/793    most recent Alert me when this article is cited Alert me if a correction is posted 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 Dai, Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Dai, Y. Articles by Grant, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 2, 2007 Accepted April 19, 2008 Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate Yun Dai, Shuang Chen, Charis A Venditti, Xin-Yan Pei, Tri K Nguyen, Paul Dent, and Steven Grant* Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia, United States Departments of Biochemistry, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia, United States Departments of Pharmacology, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia, United States * Corresponding author; email: stgrant{at}vcu.edu. Interactions between the dual Bcr/Abl and aurora kinase inhibitor MK-0457 and the histone deacetylase inhibitor vorinostat were examined in Bcr/Abl+ leukemia cells including those resistant to imatinib mesylate (IM), particularly those with the T315I mutation. Co-administration of vorinostat dramatically increased MK-0457 lethality in K562 and LAMA84 cells. Notably, the MK-0457/vorinostat regimen was highly active against primary CD34+ CML cells, Ba/F3 cells bearing various Bcr/Abl mutations (i.e., T315I, E255K, and M351T), as well as IM-resistant K562 cells exhibiting Bcr/Abl-independent, Lyn-dependent resistance. These events were associated with inactivation and downregulation of wt and mutated Bcr/Abl (particularly T315I). Moreover, treatment with MK-0457 resulted in accumulation of cells with 4N DNA content, whereas co-administration of vorinostat markedly enhanced aurora kinase inhibition by MK-0457, and preferentially killed polyploid cells. Furthermore, vorinostat also interacted with a selective inhibitor of aurora kinase A and B to potentiate apoptosis without modifying Bcr/Abl activity. Finally, vorinostat markedly induced Bim expression, while blockade of Bim induction by siRNA dramatically diminished the capacity of this agent to potentiate MK-0457 lethality. Together, these findings indicate that vorinostat strikingly increases MK-0457 activity against IM-sensitive and -resistant CML cells through inactivation of Bcr/Abl and aurora kinases, as well as by induction of Bim. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Chen, Y. Dai, X.-Y. Pei, and S. Grant Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1 Mol. Cell. Biol., December 1, 2009; 29(23): 6149 - 6169. [Abstract] [Full Text] [PDF] D. S. Boss, J. H. Beijnen, and J. H.M. Schellens Clinical Experience with Aurora Kinase Inhibitors: A Review Oncologist, August 1, 2009; 14(8): 780 - 793. [Abstract] [Full Text] [PDF]

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