Arsenite-induced Radiosensitization of Glioma Cells Is Dependent on p53 Deficiency
Yasuharu Ninomiya1, Tatsuhiko Imaoka2, Kazuhiro Daino2
1Department of Radiation Effects Research, National Institute of Radiological Sciences, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Chiba, Japan; ninomiya.yasuharu@qst.go.jp.
Background/Aim:
Arsenite is a radiosensitizer of glioma cells both in vitro and in vivo; however, the underlying mechanism of action is unclear. Radiosensitizers specific for p53-deficient tumors are a promising adjunct to radiotherapy because, unlike normal cells, many tumor cells lack p53. Previously, we demonstrated that arsenite sensitizes the p53-deficient glioma cell line U87MG-E6 to X-rays.
Materials And Methods:
Using flowcytometry, we expand these findings to p53-proficient U87MG cells exposed to heavy ion beams, including carbon and iron ions.
Results:
Arsenite sensitized U87MG-E6, but not U87MG, cells to heavy ion beams and X-rays. Cell cycle analysis indicated that sensitization of U87MG-E6 was related to an increase in the percentage of cells in the late S/G2/M phases after combined treatment with arsenite, especially when carbon ion beams were used. Induction of γH2AX was significant in U87MG-E6, but not in U87MG, cells after irradiation with carbon ion beams plus arsenite.
Conclusion:
Arsenite sensitizes cells by increasing the percentage of cells in the late S/G2/M phases after irradiation, possibly via inhibition of DNA repair in the context of p53 deficiency. The findings provide information that may be useful for the development of advanced radiotherapy protocols.
Insights
Arsenite enhances radiotherapy by sensitizing p53-deficient glioma cells to radiation, particularly heavy ion beams. This occurs by increasing cells in late S/G2/M phases, suggesting a role in DNA repair inhibition for improved cancer treatment.
Area of Science:
- Oncology
- Radiation Oncology
- Molecular Biology
Background:
- Arsenite acts as a radiosensitizer for glioma cells, but its mechanism is not fully understood.
- Radiosensitizers targeting p53-deficient tumors are valuable for radiotherapy, as many tumors lack functional p53.
- Previous studies showed arsenite sensitizes p53-deficient U87MG-E6 glioma cells to X-rays.
Purpose of the Study:
- To investigate the radiosensitizing effect of arsenite on p53-proficient U87MG cells using heavy ion beams.
- To elucidate the mechanism by which arsenite sensitizes glioma cells to radiation, focusing on cell cycle effects and DNA damage response.
Main Methods:
- Flow cytometry was used to analyze cell cycle progression in p53-proficient U87MG and p53-deficient U87MG-E6 cells.
- Cells were exposed to heavy ion beams (carbon and iron ions) and X-rays, with and without arsenite treatment.
- Gamma H2AX (γH2AX) induction was assessed as a marker of DNA double-strand breaks.
Main Results:
- Arsenite sensitized U87MG-E6 cells but not U87MG cells to both heavy ion beams and X-rays.
- Sensitization in U87MG-E6 cells correlated with an increased percentage of cells in the late S/G2/M phases after combined treatment, especially with carbon ions.
- Significant induction of γH2AX was observed in U87MG-E6 cells treated with carbon ion beams and arsenite, but not in U87MG cells.
Conclusions:
- Arsenite sensitizes glioma cells to irradiation by increasing the proportion of cells in the late S/G2/M phases, potentially through DNA repair inhibition.
- This effect is more pronounced in p53-deficient cells, highlighting a potential therapeutic strategy for specific tumor types.
- Findings support the development of advanced radiotherapy protocols utilizing arsenite as a radiosensitizer for p53-deficient gliomas.
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