Enhancement of Radiation Sensitivity of Human Squamous Carcinoma Cells by Histone Deacetylase Inhibitors

Zhang, Y., Jung, M., Dritschilo, A. and Jung, M. Enhancement of Radiation Sensitivity of Human Squamous Carcinoma Cells by Histone Deacetylase Inhibitor. Radiat. Res. 161, 667–674 (2004). Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents with potential for disruption of critical...

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Published in:Radiation research 2004-06, Vol.161 (6), p.667-674
Main Authors: Zhang, Yin, Jung, Manfred, Dritschilo, Anatoly, Jung, Mira
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Apoptosis - radiation effects
Carcinoma, Squamous Cell - pathology
Cell cycle
Cell Cycle - drug effects
Cell Cycle - radiation effects
Cell Line, Tumor - drug effects
Cell Line, Tumor - radiation effects
Cell lines
Cell Survival - drug effects
Cell Survival - radiation effects
Chromatin
Depsipeptides
DNA damage
Dose-Response Relationship, Drug
Dose-Response Relationship, Radiation
Head and Neck Neoplasms - pathology
Histone Deacetylase Inhibitors
Histones
Humans
Hydroxamic Acids - pharmacology
Irradiation
Peptides, Cyclic - pharmacology
Radiation tolerance
Radiation Tolerance - drug effects
Radiation-Sensitizing Agents - pharmacology
REGULAR ARTICLES
Squamous cell carcinoma
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Summary:Zhang, Y., Jung, M., Dritschilo, A. and Jung, M. Enhancement of Radiation Sensitivity of Human Squamous Carcinoma Cells by Histone Deacetylase Inhibitor. Radiat. Res. 161, 667–674 (2004). Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents with potential for disruption of critical cellular processes in cancer cells. Transcriptional regulation, differentiation, cell cycle arrest, radiation sensitization, and apoptosis have been observed in response to exposure to HDAC inhibitors. In the present study, we observed that several potent HDAC inhibitors, including trichostatin A, suberoylanilide hydroxamic acid, M344 (an analogue of hydroxamic acid), and the cyclic tetrapeptide, depsipeptide (FR90228), modulate cellular responses to ionizing radiation in cells of two human squamous carcinoma lines (SQ-20B and SCC-35), previously characterized as intrinsically resistant to radiation. Also exposure to IC50 concentrations of these inhibitors, radiation sensitivities were enhanced in both cell lines. Depsipeptide exhibited the greatest effect on SQ-20B cells, decreasing D0 values from 2.62 Gy to 1.64 Gy. M344 was the most active drug in sensitizing SCC-35 cells, decreasing D0 values from 1.91 Gy to 1.21 Gy. The mechanisms underlying HDAC inhibitor-induced radiosensitization were further investigated by extending trichostatin A studies to assess cell cycle distributions and levels of apoptosis. Treatment of SQ-20B cells with radiosensitizing concentrations of trichostatin A resulted in cell cycle arrest in G1 phase (>70%) and inhibition of DNA synthesis. Contrary to previous reports, induction of apoptosis was very low and caspase 3 and 9 were not activated. Taken together, these results implicate G1 arrest and inhibition of DNA synthesis in the mechanisms underlying radiation sensitization by trichostatin A and support the use of HDAC inhibitors for targeting radioresistant cancers.
ISSN:0033-7587
1938-5404
DOI:10.1667/RR3192