Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors

KF Whitecross, AE Alsop, LA Cluse… - Blood, The Journal …, 2009 - ashpublications.org
KF Whitecross, AE Alsop, LA Cluse, A Wiegmans, KM Banks, C Coomans, MJ Peart…
Blood, The Journal of the American Society of Hematology, 2009ashpublications.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 used 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 …
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-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 (ie, Bcl-2 or Bcl-XL) are likely to be the most sensitive target cell population. Our studies provide important preclinical data on the binding specificity of ABT-737 and its usefulness against primary hematologic malignancies when used as a single agent and in combination with HDACi.
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