Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors.
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.
Whitecross
Kate F
KF
Cancer Immunology Program, The Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, East Melbourne, Australia.
Alsop
Amber E
AE
Cluse
Leonie A
LA
Wiegmans
Adrian
A
Banks
Kellie-Marie
KM
Coomans
Claudia
C
Peart
Melissa J
MJ
Newbold
Andrea
A
Lindemann
Ralph K
RK
Johnstone
Ricky W
RW
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D019254:Genes, bcl-2; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D013379:Substrate Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D000077337:Vorinostat
C501332:ABT-737; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D000077337:Vorinostat