Abstract
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.
Highlights
Chemotherapy and radiotherapy are generally prescribed for the treatment of cancers, and such DNA-damaging cytotoxic therapies remain the main treatment of cancers such as osteosarcoma and breast cancer
Histone deacetylase (HDAC) was identified as a promising therapeutic target for cancer treatment as it plays a central role in chromosome structural remodeling and gene-transcriptional regulation, with altered expression and mutation of HDAC linked to tumor development and occurrence [1]
Eighteen mammalian HDACs have been identified so far [2], and have been subdivided into four different classes based on their homology with yeast HDACs
Summary
Chemotherapy and radiotherapy are generally prescribed for the treatment of cancers, and such DNA-damaging cytotoxic therapies remain the main treatment of cancers such as osteosarcoma and breast cancer. TToo uunnddeerrssttaanndd wwhheetthheerr tthhee aabboovvee--oobbsseerrvveedd VVPPAA eeffffeeccttss oonn DDSSBB mmaayy bbee aassssoocciiaatteedd wwiitthh cceelllluullaarr rraaddiioosseennssiittiivviittyy,, aa cclloonnooggeenniicc ssuurrvviivvaall aassssaayy wwaass eemmppllooyyeedd. VPA on suppressing tumor cell growth may be through its effect on DNA repair functions. It has Ibteheans bineecnreinacsrienagslinygplyropproopsoesdedththaatt theeeeffefectcot foHf DHADCAinChiibnihtoirbsiitnorthseinradthioesernasditiiozsaetinonsiotifzation of tumtourmcoerllcselolsccoucrcruerdredvivaiathtehierireefffefeccttss oonn tthhee DDNNAArreeppaiarirpapthawthawy a[y7,2[37],.23O]u. We used primary-culture cells of chemical-induced breast cancer model to detect VPA-induced radiosensitivity. This model successfully mimicked the development of human primary tumor by a chemical carcinogen, DMBA. Sensitization of tumor cells via inhibition of the DNA damage repair response may contribute a broader and more meaningful strategy to improve radio-therapy efficacy for tumor patients
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