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

Abstract

The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpression of Bcl-2 or Bcl-X(L). Herein, we used the small molecule inhibitor ABT-737 to restore sensitivity of Emu-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 Emu-myc/Mcl-1 and Emu-myc/A1 cells either as a single agent or in combination with HDACi. However, in contrast to the reported binding specificity data, Emu-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-X(L). Emu-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-X(L)) 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: Kate F Whitecross, Amber E Alsop, Leonie A Cluse, Adrian Wiegmans, Kellie-Marie Banks, Claudia Coomans, Melissa J Peart, Andrea Newbold, Ralph K Lindemann, Ricky W Johnstone
• Journal: Blood (Blood) Vol. 113 Issue 9 Pg. 1982-91 (Feb 26 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19060243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Biphenyl Compounds
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Nitrophenols
• Piperazines
• Sulfonamides
• Vorinostat

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biphenyl Compounds (administration & dosage, pharmacology)
• Cell Survival (drug effects)
• Drug Delivery Systems
• Drug Evaluation, Preclinical
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Enzyme Inhibitors (administration & dosage)
• Genes, bcl-2
• Genes, myc
• Histone Deacetylase Inhibitors
• Hydroxamic Acids (administration & dosage)
• Lymphoma (drug therapy, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nitrophenols (administration & dosage, pharmacology)
• Piperazines (administration & dosage, pharmacology)
• Substrate Specificity
• Sulfonamides (administration & dosage, pharmacology)
• Vorinostat