1. Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities.
- Author
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Newbold A, Matthews GM, Bots M, Cluse LA, Clarke CJ, Banks KM, Cullinane C, Bolden JE, Christiansen AJ, Dickins RA, Miccolo C, Chiocca S, Kral AM, Ozerova ND, Miller TA, Methot JL, Richon VM, Secrist JP, Minucci S, and Johnstone RW
- Subjects
- Acetylation drug effects, Animals, Antineoplastic Agents administration & dosage, Apoptosis drug effects, Cell Line, Tumor, Cell Survival drug effects, Enzyme Activation drug effects, Fusion Proteins, bcr-abl metabolism, HSP90 Heat-Shock Proteins metabolism, Histone Deacetylase 1 antagonists & inhibitors, Histone Deacetylase 2 antagonists & inhibitors, Histone Deacetylase 6, Histone Deacetylase Inhibitors administration & dosage, Histone Deacetylases metabolism, Humans, Hydroxamic Acids administration & dosage, Hydroxamic Acids pharmacology, Lymphoma drug therapy, Lymphoma metabolism, Lymphoma mortality, Lymphoma pathology, Mice, Vorinostat, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Histone Deacetylase Inhibitors pharmacology
- Abstract
Histone deacetylase inhibitors (HDACi) are anticancer agents that induce hyperacetylation of histones, resulting in chromatin remodeling and transcriptional changes. In addition, nonhistone proteins, such as the chaperone protein Hsp90, are functionally regulated through hyperacetylation mediated by HDACis. Histone acetylation is thought to be primarily regulated by HDACs 1, 2, and 3, whereas the acetylation of Hsp90 has been proposed to be specifically regulated through HDAC6. We compared the molecular and biologic effects induced by an HDACi with broad HDAC specificity (vorinostat) with agents that predominantly inhibited selected class I HDACs (MRLB-223 and romidepsin). MRLB-223, a potent inhibitor of HDACs 1 and 2, killed tumor cells using the same apoptotic pathways as the HDAC 1, 2, 3, 6, and 8 inhibitor vorinostat. However, vorinostat induced histone hyperacetylation and killed tumor cells more rapidly than MRLB-223 and had greater therapeutic efficacy in vivo. FDCP-1 cells dependent on the Hsp90 client protein Bcr-Abl for survival, were killed by all HDACis tested, concomitant with caspase-dependent degradation of Bcr-Abl. These studies provide evidence that inhibition of HDAC6 and degradation of Bcr-Abl following hyperacetylation of Hsp90 is likely not a major mechanism of action of HDACis as had been previously posited., (©2013 AACR.)
- Published
- 2013
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