Liu Guochao, Wang Hui, Zhang Fengmei, Tian Youjia, Tian Zhujun, Cai Zuchao, Lim David, Feng Zhihui
Department of Occupational Health and Occupational Medicine, School of Public Health, Shandong University, Jinan 250012, China.
Flinders Rural Health South Australia, Victor Harbor, SA 5211, Australia.
Int J Mol Sci. 2017 May 10;18(5):1027. doi: 10.3390/ijms18051027.
This study explored whether valproic acid (VPA, a histone deacetylase inhibitor) could radiosensitize osteosarcoma and primary-culture tumor cells, and determined the mechanism of VPA-induced radiosensitization. The working system included osteosarcoma cells (U2OS) and primary-culture cells from chemical carcinogen (DMBA)-induced breast cancer in rats; and clonogenic survival, immunofluorescence, fluorescent in situ hybridization (FISH) for chromosome aberrations, and comet assays were used in this study. It was found that VPA at the safe or critical safe concentration of 0.5 or 1.0 mM VPA could result in the accumulation of more ionizing radiation (IR)-induced DNA double strand breaks, and increase the cell radiosensitivity. VPA-induced radiosensitivity was associated with the inhibition of DNA repair activity in the working systems. In addition, the chromosome aberrations including chromosome breaks, chromatid breaks, and radial structures significantly increased after the combination treatment of VPA and IR. Importantly, the results obtained by primary-culture cells from the tissue of chemical carcinogen-induced breast cancer in rats further confirmed our findings. The data in this study demonstrated that VPA at a safe dose was a radiosensitizer for osteosarcoma and primary-culture tumor cells through suppressing DNA-double strand breaks repair function.
本研究探讨了丙戊酸（VPA，一种组蛋白去乙酰化酶抑制剂）是否能使骨肉瘤及原代培养肿瘤细胞对辐射敏感，并确定了VPA诱导辐射增敏的机制。研究体系包括骨肉瘤细胞（U2OS）以及大鼠化学致癌物（DMBA）诱导的乳腺癌原代培养细胞；本研究采用了克隆形成存活实验、免疫荧光实验、用于染色体畸变分析的荧光原位杂交（FISH）实验以及彗星实验。结果发现，安全或临界安全浓度为0.5或1.0 mM的VPA可导致更多电离辐射（IR）诱导的DNA双链断裂积累，并增加细胞辐射敏感性。VPA诱导的辐射敏感性与研究体系中DNA修复活性的抑制有关。此外，VPA与IR联合处理后，包括染色体断裂、染色单体断裂和径向结构在内的染色体畸变显著增加。重要的是，大鼠化学致癌物诱导的乳腺癌组织原代培养细胞所获得的结果进一步证实了我们的发现。本研究数据表明，安全剂量的VPA通过抑制DNA双链断裂修复功能，可作为骨肉瘤及原代培养肿瘤细胞的辐射增敏剂。
