Histone deacetylase inhibitors sensitize murine B16F10 melanoma cells to carbon ion irradiation by inducing G1 phase arrest

学位記番号：医博甲163

Histone Deacetylase Inhibitors Sensitize Murine B16F10 Melanoma Cells to Carbon Ion Irradiation by Inducing G1 Phase Arrest

Epigenetic processes, in addition to genetic abnormalities, play a critical role in refractory malignant　diseases and cause the unresponsiveness to various chemotherapeutic regimens and radiotherapy. Herein　we demonstrate that histone deacetylase inhibitors (HDACis) can be used to sensitize malignant melanoma　B16F10 cells to carbon ion irradiation. The cells were first treated with HDACis (romidepsin [FK228, depsipeptide], trichostatin A [TSA], valproic acid [VPA], and suberanilohydroxamic acid [SAHA, vorinostat]) and　were then　exposed to two types of radiation (carbon ions and gamma-rays). We found that HDACis enhanced　the radiation-induced apoptosis and suppression of clonogenicity that was induced by irradiation, having a　greater effect with carbon ion irradiation than with gamma-rays. Carbon ion irradiation and the HDACi　treatment induced G2/M and G0/G1 cell cycle arrest, respectively. Thus, it is considered that HDACi treatment enhanced the killing effects of carbon ion irradiation against melanoma cells by inducing the arrest　of G1 phase cells, which are sensitive to radiation due to a lack of DNA homologous recombination repair.　Based on these findings, we propose that pretreatment with HDACis as radiosensitizers to induce G1 arrest　combined with carbon ion irradiation may have clinical efficacy against refractory cancer