RAD51 Inhibitor and Radiation Toxicity in Vestibular Schwannoma

Torin P. Thielhelm, Aida Nourbakhsh, Scott M. Welford, Eric A. Mellon, Olena Bracho, Michael E. Ivan, Fred Telischi, Cristina Fernandez-Valle, Christine T. Dinh

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: To describe the RAD51 response (DNA repair) to radiation-induced DNA damage in patient-derived vestibular schwannoma (VS) cells and investigate the utility of RAD51 inhibitor (RI-1) in enhancing radiation toxicity. Study Design: Basic and translational science. Setting: Tertiary academic facility. Methods: VS tumors (n = 10) were cultured on 96-well plates and 16-well slides, exposed to radiation (0, 6, 12, or 18 Gy), and treated with RI-1 (0, 5, or 10 µM). Immunofluorescence was performed at 6 hours for γ-H2AX (DNA damage marker), RAD51 (DNA repair protein), and p21 (cell cycle arrest protein). Viability assays were performed at 96 hours, and capillary Western blotting was utilized to determine RAD51 expression in naïve VS tumors (n = 5). Results: VS tumors expressed RAD51. In cultured VS cells, radiation initiated dose-dependent increases in γ-H2AX and p21 expression. VS cells upregulated RAD51 to repair DNA damage following radiation. Addition of RI-1 reduced RAD51 expression in a dose-dependent manner and was associated with increased γ-H2AX levels and decreased viability in a majority of cultured VS tumors. Conclusion: VS may evade radiation injury by entering cell cycle arrest and upregulating RAD51-dependent repair of radiation-induced double-stranded breaks in DNA. Although there was variability in responses among individual primary VS cells, RAD51 inhibition with RI-1 reduced RAD51-dependent DNA repair to enhance radiation toxicity in VS cells. Further investigations are warranted to understand the mechanisms of radiation resistance in VS and determine whether RI-1 is an effective radiosensitizer in patients with VS.

Original languageEnglish (US)
JournalOtolaryngology - Head and Neck Surgery (United States)
DOIs
StateAccepted/In press - 2022

Keywords

  • cell cycle arrest
  • H2AX
  • p21
  • RAD51
  • RAD51 inhibitor
  • radiation
  • resistance
  • vestibular schwannoma
  • VS

ASJC Scopus subject areas

  • Surgery
  • Otorhinolaryngology

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