Effect of Simvastatin on Irradiated Primary Vestibular Schwannoma Cells.

HYPOTHESIS: Simvastatin enhances radiation cytotoxicity of primary vestibular schwannoma (VS) and NF2 -mutant human Schwann (HS01) cells.

BACKGROUND

Approximately 10% of VS progress after radiotherapy. Simvastatin is a lipid-lowering medication that promotes apoptosis, inhibits cell proliferation, and enhances radiation response in various cancers. In this study, we determine the effect of simvastatin on the viability of irradiated and nonirradiated primary VS and HS01 cells.

METHODS

Primary VS (N = 5) and HS01 cells were pretreated with simvastatin (0 or 1 μM) prior to irradiation (0 or 18 Gy). A cell-based assay was used to measure cell viability. Immunocytochemistry was performed for γH2AX (DNA damage marker) and RAD51 (DNA repair protein). Statistical analysis was conducted with parametric and nonparametric one-way analysis of variance tests.

RESULTS

Radiation initiated double-stranded breaks in DNA in both VS and HS01 cells. Two VS were radiation-resistant and the remaining three VS were radiation-sensitive. In response to radiation, radiation-resistant VS cells activated RAD51-mediated DNA repair. Simvastatin blocked RAD51 activation in radiation-resistant VS, increased levels of lethal DNA damage, and enhanced radiation-induced cell death. Simvastatin also enhanced radiation-induced cell death in radiation-sensitive VS cells through RAD51-independent mechanisms. However, simvastatin was not effective as a radiosensitizer in HS01 cells.

CONCLUSION

Simvastatin improved radiation response of radiation-resistant primary VS cells by inhibiting RAD51-related DNA repair. Although through RAD51-independent mechanisms, simvastatin also improved radiation response in radiation-sensitive VS cells. Additional preclinical investigations are warranted to evaluate the mechanisms of action and efficacy of statin drugs as radiosensitizers for VS patients.