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

abstract

  • 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.

authors

  • Whitecross, Kate F
  • Alsop, Amber E
  • Cluse, Leonie A
  • Wiegmans, Adrian
  • Banks, Kellie-Marie
  • Coomans, Claudia
  • Peart, Melissa J
  • Newbold, Andrea
  • Lindemann, Ralph K
  • Johnstone, Ricky W

publication date

  • February 26, 2009

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