Journal article
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
L Ellis, M Bots, RK Lindemann, JE Bolden, A Newbold, LA Cluse, CL Scott, A Strasser, P Atadja, SW Lowe, RW Johnstone
Blood | Published : 2009
Abstract
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 ly..
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Awarded by National Cancer Institute
Funding Acknowledgements
R.W.J. is a Pfizer Australia Research Fellow and was supported by the National Health and Medical Research Council of Australia (program grant 251608), the Cancer Council Victoria, the Leukemia Foundation of Australia, and the Bennelong Foundation. L. E. was supported by a postgraduate scholarship from the Leukemia Foundation of Australia. M. B. was supported by a Rubicon research grant from Netherlands Organisation for Scientific Research. A. S. was supported by the National Health and Medical Research Council of Australia (program grant 257502; Australia Fellowship) and the Leukemia & Lymphoma Society (New York, NY; Specialized Center of Research grant 7015). C. L. S. was supported by National Health and Medical Research Council of Australia RDWright Biomedical (CDA 406675).