The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats

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.

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Recent in vitro studies in cell lines have shown VPA to be a radiosensitizer in melanoma, breast cancer, osteosarcoma and colorectal cancer . Several in vivo and in vitro studies as well as clinical studies have also indicated that VPA has radiosensitizing effects for gliomas and is radioprotective to normal brain tissue .…”

2-hexyl-4-pentynoic acid (HPTA), a novel radiosensitizer to breast cancer cells through increasing the instability of DNA repair proteins

“…More recent studies have also found VPA to increase the radiosensitivity of solid malignant tumor cells, including esophagus cancer [11], lung cancer [12], prostate cancer [13], and colon cancer [14]. Our previous studies have demonstrated that 500 µM VPA increases the sensitivity of osteosarcoma U2OS cells, breast cancer MCF7 cells and breast cancer tissue-derived primary cells to radiation therapy [15,16]. The mechanism involves inhibiting BRCA1-Rad51-mediated homologous recombination (HR) and Ku80-mediated non-homologous end joining (NHEJ) repairs, resulting in DSBs accumulation and tumor cell death.…”

“…At the endpoint, cells were xed with ethanol and stained with 0.1% crystal violet in 20% methanol for 30 min. The detailed method was described in our previous publications [15,16]. The number of cell colonies was counted and cell survival was presented by the cell survival fraction (SF), with SF= (the number of clones/seeded cells)/plating e ciency (PE).…”

“…Cells were seeded in an eight-well chamber at a density of 3 × 10 4 cells per well. The methods were described in detail in our previous publications [15,16]. The primary antibodies used for immunoblotting analysis speci c to γH 2 AX (1:500; 05-636, EMD Millipore), 53BP1(1:1000; NB100-304, Gene Tex), Rad51…”

Developing a radiosensitivity gene signature for Caucasian patients with breast cancer

“…In the era of precision medicine, biology-driven personalized radiotherapy in breast cancer using biomarkers to guide exclusive radiotherapy and combination therapy have started to emerge (9,10). Several biomarkers based on single gene or molecular expression with specificity in predicting the survival benefit have been developed and validated (11)(12)(13)(14)(15). Gene signatures (which refers to a group of genes), have been used to identify radiosensitive patients in numerous types of cancer, including glioblastoma, cervical, colorectal, and head and neck cancer (16)(17)(18)(19)(20).…”