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


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-naïve 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.


CONCLUSIONS
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.
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.
Jin Ho
JH
Kim
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ; Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea.
Il Han
IH
Kim
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.
Jin Hee
JH
Shin
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.
Hak Jae
HJ
Kim
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ; Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
In Ah
IA
Kim
Histone deacetylase inhibitors; Preclinical drug evaluation; Radiation-sensitizing agents