Journal article
Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors
KF Whitecross, AE Alsop, LA Cluse, A Wiegmans, KM Banks, C Coomans, MJ Peart, A Newbold, RK Lindemann, RW Johnstone
Blood | Published : 2009
Abstract
The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpresssion of Bcl-2 or Bcl-XL. Herein, we used the small molecule inhibitor ABT-737 to restore sensitivity of Eμ-myc lymphomas overexpressing Bcl-2 or Bcl-X L 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..
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Awarded by NHMRC (Canberra, Australia)
Funding Acknowledgements
[ "We thank David Huang, Andreas Strasser, Clare Scott, Jerry Adams, Suzanne Cory, and Alan Harris from the Walter and Eliza Hall Institute for helpful advice, Eu-myc mice, and cDNAs for Bcl-2, Bcl-X<INF>L</INF>, Bcl-w, Mcl-1, and A1. We thank Drs Saul Rosenberg, Steve Elmore, Alex Shoemaker, and Victoria Richon for helpful advice and providing reagents. Vorinostat was kindly provided by Merck, and ABT-737 was kindly provided by Abbott Laboratories.", "R.W.J. is a Pfizer Australia Research Fellow and is supported by a NHMRC (Canberra, Australia) Program Grant 251608, the Cancer Council Victoria (Melbourne, Australia), the Leukemia Foundation of Australia (Box Hill, Australia), and the Bennelong Foundation (Melbourne, Australia)." ]