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. Author manuscript; available in PMC: 2026 Feb 24.
Published in final edited form as: Otol Neurotol. 2025 Feb 24;46(7):842–847. doi: 10.1097/MAO.0000000000004469

Effect of Simvastatin on Irradiated Primary Vestibular Schwannoma Cells

Matthew Wiefels 1, Olena Bracho 1, Mikhail Marasigan 1, Fred Telischi 1,2, Michael E Ivan 2,3, Scott Welford 2,4, Cristina Fernandez-Valle 5, Christine T Dinh 1,2
PMCID: PMC12342339  NIHMSID: NIHMS2076090  PMID: 40059781

Abstract

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 non-irradiated primary VS and HS01 cells.

Methods:

Primary VS (N=5) and HS01 cells were pre-treated 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 non-parametric 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 3 VS were radiation-sensitive. In response to radiation, radiation-resistant VS cells activated RAD51-mediated DNA repair to evade cell death. 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 pre-clinical investigations are warranted to evaluate the mechanisms of action and efficacy of statin drugs as radiosensitizers for VS patients.

Keywords: simvastatin, statin, radiation, radiotherapy, NF2, vestibular schwannoma, VS, RAD51, DNA repair, H2AX, DNA damage

Introduction

Vestibular schwannomas (VS) are intracranial, benign tumors that derive from Schwann cells of cranial nerve VIII. Although 93% of cases are sporadic and affect either the right or left eighth cranial nerve, approximately 7% occur bilaterally as part of the genetic syndrome called NF2-related schwannomatosis (NF2)1,2. Sporadic VS is relatively common and affects 1 in 2,000 adults in their lifetime, with prevalence increasing with age3,4. Patients afflicted with these tumors commonly present with hearing loss, tinnitus, and dizziness5. However, large tumors may compress the brainstem and cause neurological complications, such as hydrocephalus, ataxia, and stroke6,7. Management of sporadic VS can include observation with watch-and-scan approach, microsurgical resection, and/or radiotherapy, depending on a variety of factors including age, clinical presentation, tumor size, tumor growth rate, and patient preferences8-10.

Stereotactic radiosurgery (SRS) is a form of radiotherapy that delivers precise and focused radiation beams to the tumor while reducing radiation exposure to adjacent normal tissue, like the brainstem and cochlea. SRS has an excellent tumor control rate of approximately 94% at 10 years; however, the long term tumor control rates declines significantly to ~80% for larger VS11, to 66-69% for fast-growing tumors12,13, and to ~52% for NF2-associated VS14 at 10-15 year follow-up. Although the mechanisms of radiation resistance have not been fully elucidated in VS, it is believed that radiation resistance may develop because of tumor hypoxia, mutations affecting tumor suppressor and oncogenes, robust activation of DNA repair mechanisms, prolonged cell cycle arrest, aberrant expression of cell cycle checkpoint proteins, cumulative effects of merlin deficiency on cell proliferation pathways, and/or radiation dosage and fractionation protocol used15.

Statin drugs inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase) and are known best for their cholesterol lowering properties16. When compared to hydrophilic statins, lipophilic statins, such as simvastatin, can more readily cross the blood brain barrier and treat intracranial tumors16. Statin drugs also exert anti-proliferative effects in several types of cancers by slowing cell cycle progression and inducing apoptosis through multiple signaling pathways17. Furthermore, simvastatin can enhance radiation response in various tumors by promoting double-strand breaks (DSB) in DNA and inhibiting DNA repair enzymes, among other pathways18-21. In this study, we analyze the effect of simvastatin and radiation on the viability and expression of γH2AX (a marker of DNA DSBs) and RAD51 (a DNA repair enzyme) in primary VS and NF2-mutant human Schwann (HS01) cells.

Materials and Methods

Cell Culture

Fresh VS tumors (N=5) were harvested from patients undergoing surgery for sporadic, unilateral VS through the University of Miami Institutional Review Board Approved Protocol #20150637. Patients were >18 years of age without prior treatment with radiation, surgery, or chemotherapy. Tumors were placed in chilled Dulbecco’s Modified Eagle Medium (DMEM; Gibco) and transported to the research laboratory, where tumors were enzymatically dissociated with collagenase (150 U/ml; Sigma Aldrich) and dispase II (2.5 μg/ml; Sigma Aldrich) in DMEM overnight at 37°C and 5% CO2. Primary VS cells were then triturated, filtered, and cultured in Schwann media (ScienCell) with 5% fetal bovine serum (FBS; Avantor Seradigm) and 1% penicillin/streptomycin in T25 flasks coated with 0.01% poly-L-ornithine (PLO; Sigma) and laminin (25 μg/ml; ThermoFisher).

Because primary VS cells are extracted from tumors of different patients, they are genetically heterogenous and genetically unaltered. Most VS tumors harbor at least one NF2 mutation22-24. Unlike primary VS cells, HS01 cells are derived from normal human Schwann cells and transformed with a lentivirus delivering small hair pin ribonucleic acids (lenti-NF2-shRNA) that silence NF2 gene expression, impair merlin production, and promote cell proliferation24. HS01 cells are used as a model cell line to study schwannoma biology and screen potential therapies for NF2 and VS25,26. They are cultivated in Schwann media (ScienCell) on CellBIND dishes (Corning)24.

Treatment Conditions

Simvastatin (Selleckchem) was solubilized in dimethyl sulfoxide (DMSO; Sigma-Aldrich), a widely used solvent. For experiments, primary VS and HS01 cells were treated with either 0.0005% DMSO or simvastatin (1 μM) in maintenance media (DMEM with 10% FBS and 1% penicillin/streptomycin) and cultivated at 37 °C, 5% CO2. After 24 hours, cells were exposed to 0 Gy or 18 Gy of radiation using the RS225 irradiator (XStrahl), which delivers a cone-shaped Xray beam in the vertical plane (195kV, 10 mA, 0.5 mm Cu filter, ~0.98 Gy/min). Cells were then incubated further at 37 °C, 5% CO2. Immunocytochemistry was performed at 6 hours post-irradiation, and viability assays were performed at 72 hours post-irradiation. Treatment conditions were presented as control (0 Gy + DMSO), simvastatin alone (0 Gy + simvastatin), radiation alone (18 Gy + DMSO), and radiation + simvastatin (18 Gy + simvastatin)

Immunocytochemistry

For immunocytochemistry, primary VS and HS01 cells were grown on 16-well chamber slides (Nunc Labtek; ThermoFisher) pre-coated with 0.01% PLO and laminin (25 μg/ml) at a density of 10,000 cells / well. After 48 hours, cells were exposed to 4 different treatment conditions, as described above. Cells were fixed in 4% paraformaldehyde at 6 hours post-irradiation. Subsequently, cells were blocked and permeabilized with 1% Triton X-100 and 5% normal donkey serum (Sigma Aldrich) in phosphate buffered saline (PBS) for 30 minutes. Slides were then incubated with primary antibodies anti-γH2AX mouse monoclonal antibody (DNA damage marker; 1:100; GeneTex) and anti-RAD51 rabbit monoclonal antibody (DNA repair marker; 1:1000; Abcam) in 0.2% Triton X-100 and 1% normal donkey serum at 4°C overnight. Slides were then exposed to AlexaFluor 488-conjugated anti-mouse and AlexaFluor 594-conjugated anti-rabbit IgG monoclonal secondary antibodies (1:500; ThermoFisher) for 1 hour at room temperature. Cell nuclei were stained with diamidino-2-phenylindole (DAPI; Abcam) for 15 minutes at room temperature. Slides were cover-slipped using anti-fade mounting medium (Fluoromount; Sigma Aldrich), and representative images were obtained with fluorescent microscopy (BioTek Lionheart FX Automated Microscope; Agilent, Santa Clara, California, United States). Cell analysis was performed using Gen5 software (BioTek). The number of γH2AX and RAD51 nuclear foci were quantified using the Gen5 spot counting module (BioTek).

Viability Assay

For viability assays, primary VS and HS01 cells were cultured on 384-well CellBIND plates coated with 0.01% PLO and laminin (25 μg/ml) at a density of 5,000 cells per well (n=6 replicates per treatment condition). After 48 hours, cells were exposed to 4 different treatment conditions, as described above. Viability was measured 72 hours post-irradiation using a cell-based assay (CellTiter-Glo; Promega) and quantified using a luminometer (GloMax Discover) in relative luminescence units (RLU).

Statistical Analysis

Parametric and non-parametric one-way analysis of variance (ANOVA) tests were utilized to analyze differences in viability, γH2AX and RAD51 in 5 primary VS and HS01 cells. Tukey post-hoc testing and Bonferroni correction was applied for multiple comparisons. Significance was set at p<0.05. Statistical analysis was performed using SAS Studio.

Results

HS01 Cells

Viability measurements for HS01 cells are displayed in Figure 1A. Simvastatin alone did not significantly reduce viability, when compared to control (p=0.3939). Both radiation alone and radiation + simvastatin conditions caused significant reductions in HS01 viability (p=0.0011 and p=0.0002, respectively); however, there were no significant differences between these two treatment groups (p=0.8353).

Figure 1. HS01 Cells.

Figure 1.

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HS01 cells were exposed to 4 different treatments: control, simvastatin alone, radiation alone, or radiation + simvastatin. [A] Viability was performed at 72 hours. [B-C] Immunocytochemistry was performed for γH2AX and RAD51 at 6 hours. Overall, radiation alone reduced viability of HS01 cells by initiating double-strand breaks in DNA without RAD51 activation. Simvastatin did not act as a radiosensitizer for HS01 cells as the differences in viability, γH2AX and RAD51 foci were not significantly different between radiation alone and radiation + simvastatin conditions. Bar represents mean. Error bars represent standard error. ** p<0.01. *** p<0.001. NS, not significant. RLU, relative luminescence units.

Immunocytochemistry results for HS01 cells are displayed in Figures 1B and 1C. In HS01 cells, both radiation alone and radiation + simvastatin conditions caused significant increases in the number of γH2AX nuclear foci / cell, when compared to control (p<0.0001 and p<0.0001, respectively); however, there was no difference between these two conditions (p=0.6069) (Figure 1B). When compared to control, HS01 cells did not upregulate the number of RAD51 nuclear foci 6 hours post-irradiation when treated with simvastatin alone (p=0.0590), radiation alone (p=0.9798), and radiation + simvastatin (p=1.0000) (Figure 1C).

Primary VS Cells

A reduction in tumor volume by ≥15% is a clinical threshold used in NF2 and VS clinical trials to define treatment response. We divided the 5 primary VS cultures into two groups based on their viability response to 18 Gy of radiation. VSA78 and VSB11 were grouped as radiation-resistant VS as viability responses to 18 Gy were −11.7% and −1.8%, respectively. VSB12, VSB14, and VSB16 were categorized as radiation-sensitive VS because viability responses to 18 Gy were −21.8%, −21.6%, and −15.8%, respectively.

Viability responses of radiation-resistant and radiation-sensitive VS were displayed in Figure 2A. When compared to control, radiation-sensitive primary VS demonstrated significant reductions in viability in the simvastatin alone (p<0.0001), radiation alone (p<0.0001), and radiation + simvastatin (p<0.0001) conditions. In addition, radiation + simvastatin caused greater decreases in the viability of radiation-sensitive VS, when compared to radiation alone (p=0.0057).

Figure 2. Primary VS Cells.

Figure 2.

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Radiation-resistant and radiation-sensitive VS cells were exposed to 4 different treatments: control, simvastatin alone, radiation alone, or radiation + simvastatin. [A] Viability was performed at 72 hours. [B-C] Immunocytochemistry was performed for γH2AX and RAD51 at 6 hours. Overall, radiation alone initiated double-strand breaks in DNA in both VS groups. However, radiation-resistant VS cells mounted a robust RAD51 response and less DNA damage. In radiation-resistant VS, simvastatin blocked RAD51 activation, increased DNA damage, and enhanced radiation-induced cell death. Although simvastatin also enhanced radiation response in radiation-sensitive cells, the mechanism is RAD51-independent. Bar represents mean. Error bars represent standard error. ** p<0.01. *** p<0.001. NS, not significant. RLU, relative luminescence units.

In radiation-resistant VS, radiation alone did not significantly reduce viability, when compared to control (p=0.9832). However, radiation-resistant VS demonstrated significant reductions in viability when treated with simvastatin alone (p=0.0019) and radiation + simvastatin (p=0.0001) conditions. Furthermore, radiation + simvastatin caused a greater reduction in viability in radiation-resistant VS cultures, when compared to radiation alone (p=0.0046).

Immunocytochemistry results for primary VS cells are shown in Figure 2B and 2C. Both radiation-resistant and radiation-sensitive VS groups demonstrated significant upregulations of γH2AX nuclear foci / cell when treated with radiation alone and radiation + simvastatin (p<0.0001) conditions (Figure 2B). Radiation + simvastatin caused higher levels of γH2AX foci in radiation-resistant VS, when compared to radiation alone (p<0.0001). In contrast, radiation + simvastatin caused lower levels of γH2AX foci in radiation-sensitive VS, when compared to radiation alone (p<0.0001).

In radiation-resistant VS, RAD51 nuclear foci / cell increased significantly after exposure to radiation alone (p<0.0001) (Figure 2C). However, radiation + simvastatin caused a significant reduction in RAD51 foci / cell in radiation-resistant VS cells, when compared to radiation alone (p<0.0001). Radiation-sensitive VS did not demonstrate significant differences in RAD51 foci/cell across the 4 treatment conditions (p>0.05). Representative immunocytochemistry images for VSA78 are shown in Figure 3.

Figure 3. Immunocytochemistry for γH2AX and RAD51 in Primary VS.

Figure 3.

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Primary VS cells were exposed to 4 different treatments: control, simvastatin alone, radiation alone, or radiation + simvastatin. Immunocytochemistry was performed at 6 hours for γH2AX (green), RAD51 (red), and DAPI nuclear stain (blue). Representative 20X fluorescent images are shown for VSA78.

Discussion

Statin drugs, known for their cholesterol reducing effects, can exert anti-tumor properties in several cancers by promoting cell death through various pathways17,27-30. Recent studies have shown that statin drugs, specifically simvastatin, can act as radiosensitizers by inhibiting RAD51 and other DNA repair enzymes18-21,31,32. In prostate and breast cancer, simvastatin sensitizes radioresistant cells by compromising DNA repair and enhancing DNA damage post-irradiation18,19,21,33. Simvastatin also increases radiation sensitivity of colorectal cancer20. In this study, we investigate simvastatin for the aforementioned reasons and because simvastatin is a lipophilic statin that can readily cross the blood-brain barrier and reach intracranial tumors such as VS34.

Radiation Alone

Radiation response varies among VS and likely depends on the cell cycle phase, upregulation of DNA repair and sensor proteins, deactivation of cell cycle checkpoint regulator proteins, oncogene activation, and upregulation of cell survival proteins that prevent apoptosis15,35-37. Our results found two primary VS, VSA78 and VSB11, to be more resistant to radiation than the remaining 3 VS. Thus, we focused our discussion on HS01, radiation-sensitive VS and radiation-resistant VS.

Our experiments in HS01 and radiation-sensitive VS cells showed that radiation alone can reduce viability of cells by initiating lethal DSBs in DNA, as demonstrated by increases in γH2AX nuclear foci. In addition, radiation alone did not significantly activate RAD51 (DNA repair protein) in HS01 and radiation-sensitive VS cells. This finding is complementary to viability and γH2AX results and suggests that HS01 and radiation-sensitive VS cells are more susceptible to radiation-induced cell death as they cannot mount a strong DNA repair response through RAD51 activation.

In radiation-resistant VS cells, radiation alone also initiated high levels of lethal DNA DSBs. However, unique to these cells, radiation-resistant VS mounted a robust RAD51 response to radiation, thereby activating RAD51-mediated DNA repair to evade cell death. This finding is consistent with viability assays that showed radiation alone did not significantly reduce viability of radiation-resistant VS cells. Furthermore, the number of γH2AX foci was also lower in radiation-resistant VS cells, when compared to radiation-sensitive VS, suggesting that the increased RAD51 activity in radiation-resistant VS cells may be critical for reducing lethal DNA DSBs and promoting survival of these cells.

Simvastatin Alone

As expected, simvastatin alone did not initiate relevant changes in viability, γH2AX foci and RAD51 foci of non-irradiated HS01 cells. However, simvastatin alone caused significant reductions in viability of radiation-resistant and radiation-sensitive VS cells without appreciable changes in γH2AX and RAD51 foci. These findings suggest that simvastatin can promote cell death in non-irradiated VS cells through other mechanisms, possibly by disrupting cell cycle progression, promoting oxidative stress, and activating autophagy and apoptosis-related pathways17,27-30,38-40. Statin drugs may also damage cell membranes of neoplastic cells by reducing membrane cholesterol content38,41. Further investigations are warranted to elucidate the cell death mechanisms of simvastatin in non-irradiated primary VS cells.

Radiation and Simvastatin

HS01 cell and radiation-sensitive primary VS cells had the greatest reductions in viability when treated with radiation + simvastatin, when compared to control. However, HS01 viability, γH2AX foci and RAD51 foci were not significantly different between radiation alone and radiation + simvastatin conditions, indicating that simvastatin is not an effective radiosensitizer for HS01 cells. In contrast, radiation + simvastatin reduced viability of radiation-sensitive VS cells nearly 2-fold over simvastatin alone and radiation alone without significant effects on RAD51 activation. These findings suggest that the cytotoxic effects of simvastatin may be additive to radiation, rather than synergistic, and may involve pro-death pathways unrelated to RAD51 inhibition. Although we expected radiation-sensitive VS to display the highest levels of γH2AX foci when treated with radiation + simvastatin, these cells showed a significant reduction in γH2AX foci with radiation + simvastatin, when compared to radiation alone. This unexpected finding may be related to the time point when γH2AX foci was measured (i.e., 6 hours), and γH2AX levels may show different trends at earlier and later time points. Regardless of γH2AX levels, the primary outcome was viability and radiation + simvastatin caused the greatest reductions in viabilities in these radiation-sensitive VS cells.

The viability of radiation-resistant VS cells treated with radiation + simvastatin was significantly lower than the radiation alone condition, suggesting that simvastatin may have a potential role in overcoming radiation-resistance in VS tumors. This finding is complemented by immunocytochemistry results that demonstrate that simvastatin can block radiation-induced activation of RAD51 and increase lethal DNA DSBs. A diagram depicting the mechanism of action of simvastatin in radiation-resistant VS is displayed in Figure 4. However, simvastatin’s mechanisms of action in radiation-resistant VS are likely distinct in non-irradiated and irradiated cells, as simvastatin alone caused decreases in viability without appreciable changes in γH2AX and RAD51. Further investigation into the mechanisms of simvastatin overall in primary VS are warranted.

Figure 4. Mechanisms of Action for Simvastatin and Radiation in Primary VS.

Figure 4.

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Ionizing radiation causes lethal double-stranded DNA (dsDNA) breaks in primary VS cells, thus initiating activation of the DNA repair protein RAD51. Radiation-resistant VS cells produce a more robust activation of RAD51, allowing VS cells to repair DNA damage through homologous recombination and survive lethal effects of radiation. Simvastatin can block RAD51 activation in radiation-resistant VS cells, prevent DNA repair, and enhance radiation-induced cell death in primary VS.

The limitations of this pilot study are the in vitro design, small sample size of primary VS, and assessment of viability, DNA damage, and DNA repair at single time points after radiation. Although it is an in vitro study, use of primary VS cells from patient-derived VS is advantageous for understanding tumor heterogeneity and impact of a new class of therapy. Nonetheless, simvastatin may have potential as radiosensitizers in VS, and larger preclinical studies may lead to the translation of statin drugs to VS clinical trial.

Conclusions

Simvastatin treatment improves radiation response of radiation-resistant primary VS cells by blocking RAD51-mediated DNA repair. Simvastatin also enhances radiation response in radiation-sensitive primary VS cells through mechanisms independent of RAD51 inhibition. Further investigations elucidating the mechanisms of action and effectiveness of statin drugs as radiosensitizers may lead to novel therapies for VS patients.

Sources of Funding:

University of Miami Department of Otolaryngology

National Institutes of Health [K08DC017508 to C.T.D]

Sylvester Comprehensive Cancer Center [National Institutes of Health K08DC017508 supplement to C.T.D].

National Institutes of Health [R25DC020726 to M.W.]

Footnotes

Disclosure: No relevant conflicts of interest.

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