Submitted October 22, 2008
Accepted March 31, 2009
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 Ellis, Michael Bots, Ralph K. Lindemann, Jessica E. Bolden, Andrea Newbold, Leonie A. Cluse, Clare L. Scott, Andreas Strasser, Peter Atadja, Scott W. Lowe, and Ricky W. Johnstone*
Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, East Melbourne, Victoria, Australia
The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
Novartis Institutes for BioMedical Research Inc., Cambridge, MA, United States
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
University of Melbourne, Parkville, Victoria, Australia
* Corresponding author; email: ricky.johnstone{at}petermac.org.
LAQ824 and LBH589 (panobinostat) are histone deacetylase inhibitors (HDACi) developed as cancer therapeutics. Herein we have utilized the Eµ-myc transgenic model of pre-B/B cell lymphoma to identify the molecular mechanisms required for their anti-tumor 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 the p53 tumor suppressor. Blocking the death receptor pathway had no effect on the apoptosis-inducing and therapeutic activities of LAQ824 and LBH589. However, overexpression of Bcl-2 or Bcl-XL protected Eµ-myc lymphoma cells from HDACi-induced killing and suppressed their therapeutic activities. Deletion of apaf-1 or caspase-9, essential components of the apoptosome, delayed HDACi-induced lymphoma killing in vitro and in vivo, associated with suppression of a number of morphological indicators of apoptosis, but did not provide long-term resistance to LAQ824 or LBH589 and failed to inhibit the therapeutic activities of these compounds. Eµ-myc lymphoma cells lacking a functional apoptosome displayed morphological and biochemical features of autophagy following 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 positive therapeutic outcome. Our data indicate that damage to the mitochondria is the key molecular event necessary for LAQ824 and LBH589 to mediate tumor cell death and a robust therapeutic response.
