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Blood, 9 July 2009, Vol. 114, No. 2, pp. 380-393. Prepublished online as a Blood First Edition Paper on April 21, 2009; DOI 10.1182/blood-2008-10-182758. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-10-182758v1 114/2/380    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Ellis, L. Articles by Johnstone, R. W. PubMed PubMed Citation Articles by Ellis, L. Articles by Johnstone, R. W. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy Leigh Ellis1,2, Michael Bots1, Ralph K. Lindemann1, Jessica E. Bolden1, Andrea Newbold1, Leonie A. Cluse1, Clare L. Scott3, Andreas Strasser3, Peter Atadja4, Scott W. Lowe5, and Ricky W. Johnstone1,6 1 Cancer Therapeutics Program, Gene Regulation Laboratory, Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, East Melbourne, Australia; 2 John Curtin School of Medical Research, Australian National University, Canberra, Australia; 3 Walter and Eliza Hall Institute, Melbourne, Australia; 4 Novartis Institutes for BioMedical Research, Cambridge, MA; 5 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; and 6 University of Melbourne, Parkville, Australia LAQ824 and LBH589 (panobinostat) are histone deacetylase inhibitors (HDACi) developed as cancer therapeutics and we have used the Eµ-myc lymphoma model to identify the molecular events required for their antitumor effects. Induction of tumor cell death was necessary for these agents to mediate therapeutic responses in vivo and both HDACi engaged the intrinsic apoptotic cascade that did not require p53. Death receptor pathway blockade had no effect on the therapeutic activities of LAQ824 and LBH589; however, overexpression of Bcl-2 or Bcl-XL protected lymphoma cells from HDACi-induced killing and suppressed their therapeutic activities. Deletion of Apaf-1 or Caspase-9 delayed HDACi-induced lymphoma killing in vitro and in vivo, associated with suppression of many biochemical indicators of apoptosis, but did not provide long-term resistance to these agents and failed to inhibit their therapeutic activities. Eµ-myc lymphomas lacking a functional apoptosome displayed morphologic and biochemical features of autophagy after treatment with LAQ824 and LBH589, indicating that, in the absence of a complete intrinsic apoptosis pathway involving apoptosome formation, these HDACi can still mediate a therapeutic response. Our data indicate that damage to the mitochondria is the key event necessary for LAQ824 and LBH589 to mediate tumor cell death and a robust therapeutic response. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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