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.
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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)
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Chemical References |
- ABT-737
- Biphenyl Compounds
- Enzyme Inhibitors
- Histone Deacetylase Inhibitors
- Hydroxamic Acids
- Nitrophenols
- Piperazines
- Sulfonamides
- Vorinostat
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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
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