Abstract
Background: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). Methods: Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. Results: Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. Conclusions: Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.
Document Type
Article
Publication Date
5-2023
Digital Object Identifier (DOI)
https://doi.org/10.3390/cancers15102818
Funding Information
This research was funded by the American Neurotology Society Research Grant to C.T.D., the North American Skull Base Society Research Grant to C.T.D. and F.T., the Alpha Omega Alpha Postgraduate Research Fellowship Award to A.N., the American Neurotology Society Research Grant to A.N., the NIH/NIDCD K08DC017508 to C.T.D., NIH/NIDCD T32DC015995 to X.Z.L., NIH/NCI Sylvester Comprehensive Cancer Center K-supplement grant to C.T.D., and awards from the Children’s Tumor Foundation and Department of Defense W81-15-1-0446 to C.F.V. The APC was funded by the NIH/NCI Sylvester Comprehensive Cancer Center K-supplement grant. P.V.M. received funding from The Miami Project to Cure Paralysis, the Indiana State Department of Health (grants 33997 and 43547), and the Department of Neurosurgery from University of Kentucky.
Repository Citation
Dinh, Christine T.; Chen, Si; Nourbakhsh, Aida; Padgett, Kyle; Johnson, Perry; Goncalves, Stefania; Bracho, Olena; Bas, Esperanza; Bohorquez, Jorge; Monje, Paula V.; Fernandez-Valle, Cristina; Elsayyad, Nagy; Liu, Xuezhong; Welford, Scott M.; and Telischi, Fred, "Single Fraction and Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, and Reduced Viability of Merlin-Deficient Schwann Cells" (2023). Markey Cancer Center Faculty Publications. 389.
https://uknowledge.uky.edu/markey_facpub/389
Notes/Citation Information
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).