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Blood, 26 February 2009, Vol. 113, No. 9, pp. 1982-1991. Prepublished online as a Blood First Edition Paper on December 5, 2008; DOI 10.1182/blood-2008-05-156851. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-05-156851v1 113/9/1982    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 Whitecross, K. F. Articles by Johnstone, R. W Search for Related Content PubMed PubMed Citation Articles by Whitecross, K. F. Articles by Johnstone, R. W Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 16, 2008 Accepted November 10, 2008 Defining the target specificity of ABT-737 and synergistic anti-tumor activities in combination with histone deacetylase inhibitors Kate F. Whitecross, Amber E Alsop, Leonie A Cluse, Adrian Wiegmans, Kellie-Marie Banks, Claudia Coomans, Melissa J. Peart, Andrea Newbold, Ralph K. Lindeman, and Ricky W Johnstone* Cancer Immunology Program, The Peter MacCallum Cancer Centre, East Melbourne, Australia Department of Biological Sciences, Columbia University, New York, NY, United States National Center for Tumor Diseases and German Cancer Research Center, Department of Translational Oncology, Heidelberg, Germany University of Melbourne, Parkville, Australia * Corresponding author; email: ricky.johnstone{at}petermac.org. The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpresssion of Bcl-2 or Bcl-XL. Herein, we utilised the small molecule inhibitor ABT-737 to restore sensitivity of Eµ-myc lymphomas overexpressing Bcl-2 or Bcl-XL to vorinostat and valproic acid (VPA). Combining low dose ABT-737 with vorinostat or VPA resulted in synergistic apoptosis of these cells. ABT-737 was ineffective against Eµ-myc/Mcl-1 and Eµ-myc/A1 cells either as a single agent or in combination with HDACi. However, in contrast to the reported binding specificity data, Eµ-myc/Bcl-w lymphomas were insensitive to ABT-737 used alone or in combination with HDACi indicating that the regulatory activity of ABT-737 is restricted to Bcl-2 and Bcl-XL. Eµ-myc lymphomas that expressed Bcl-2 throughout the tumorigenesis process were especially sensitive to ABT-737, while those forced to overexpress Mcl-1 were not. This supports the notion that tumor cells "addicted" to ABT-737 target proteins (i.e. Bcl-2 or Bcl-XL) are likely to be the most sensitive target cell population. Our studies provide important pre-clinical data on the binding specificity of ABT-737 and its usefulness against primary haematological malignancies when used as a single agent and in combination with HDACi. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Bots and R. W. Johnstone Rational Combinations Using HDAC Inhibitors Clin. Cancer Res., June 15, 2009; 15(12): 3970 - 3977. [Abstract] [Full Text] [PDF]

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