Cancer Res Treat.  2013 Dec;45(4):334-342.

Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041

• Kim JH
• Kim IH
• Shin JH
• Kim HJ
• Kim IA

Abstract

PURPOSE
This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation.
MATERIALS AND METHODS
The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution.
RESULTS
TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naive cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest.
CONCLUSION
TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained.

Keyword

Histone deacetylase inhibitors; Radiation-sensitizing agents; Preclinical drug evaluation

MeSH Terms

Acetylation
Blotting, Western
Cell Cycle
Drug Evaluation, Preclinical
Flow Cytometry
Histone Deacetylase Inhibitors*
Histone Deacetylases*
Histones*
Humans
Lung Neoplasms
Radiation Tolerance
Radiation-Sensitizing Agents
Histone Deacetylase Inhibitors
Histone Deacetylases
Histones
Radiation-Sensitizing Agents

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