title: The histone deacetylase inhibitor, Trichostatin A, enhances radiation sensitivity and accumulation of gammaH2A.X.
abstract: Histone deacetylase inhibitors have been shown to induce numerous biologic effects including, altering cell cycle distribution, cytostasis and in certain cases apoptosis. Given their ability to disrupt critical biological processes in cancer cells, these agents are emerging as potential therapeutics for cancer. Recently, it has been identified that histone deacetylase inhibitors can also efficiently enhance the radiation sensitivity of cells, both in vitro and in vivo. In this study, we investigated whether the potent histone deacetylase inhibitor, Trichostatin A, modulates the radiation sensitivity of human erythroleukemic K562 cells. The endpoints we used were clonogenic survival, apoptosis and gammaH2AX immunoprecipitations of soluble chromatin. The findings from clonogenic survival assays indicated that incubation with Trichostatin A 24 hours prior to irradiation enhances the radiation sensitivity of K562 cells. The dose modification factors ranged from 1.1 when cells were incubated with 0.1 microM Trichostatin A to 2.3 at 1 microM Trichostatin A. Similarly, caspase-3 and caspase-7 assays indicated that Trichostatin A potentiates radiation-induced apoptosis in K562 cells, in a concentration dependent manner. Our results suggest the modulation of radiation effects observed at the lower Trichostatin A concentrations was associated with histone hyperacetylation and changes in phosphorylated gammaH2A.X formation on euchromatin. In contrast, at the higher Trichostatin A concentrations mechanisms such as drug-mediated cytotoxicity and G1 cell cycle arrest, contributed to the sensitization effect. More generally, our findings are consistent with those from recent studies and support the development of histone deacetylase inhibitors for use as radiation sensitizers, particularly for targeting radioresistant cancers.
authors.affiliation: Molecular Radiation Biology, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Victoria, Australia.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Karagiannis
authors.forename: K N
authors.initials: KN
authors.lastname: Harikrishnan
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D005720:Gamma Rays; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020014:K562 Cells / Q000187:drug effects / Q000528:radiation effects; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
chemical_list: D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010750:Phosphoproteins; C012589:trichostatin A; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases