CORM‑2 reduces cisplatin accumulation in the mouse inner ear and protects against cisplatin-induced ototoxicity

Ah-Ra Lyu; Soo Jeong Kim; Min Jung Park; Yong-Ho Park

doi:10.1016/j.jare.2023.11.020

CORM‑2 reduces cisplatin accumulation in the mouse inner ear and protects against cisplatin-induced ototoxicity

J Adv Res. 2023 Nov 27:S2090-1232(23)00358-2. doi: 10.1016/j.jare.2023.11.020. Online ahead of print.

Authors

Ah-Ra Lyu¹, Soo Jeong Kim¹, Min Jung Park², Yong-Ho Park³

Affiliations

¹ Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
² Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea. Electronic address: mjpark@cnu.ac.kr.
³ Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea. Electronic address: parkyh@cnu.ac.kr.

PMID: 38030129
DOI: 10.1016/j.jare.2023.11.020

Abstract

Introduction: Cisplatin is a life-saving anticancer compound used to treat multiple solid malignant tumors, while it causes permanent hearing loss. There is no known cure, and the FDA has not approved any preventative treatment for cisplatin-based ototoxicity.

Objectives: This study investigated whether the carbon monoxide (CO)-releasing tricarbonyldichlororuthenium (II) dimer, CORM-2, reverses cisplatin-induced hearing impairment and reduces cisplatin accumulation in the mouse inner ear.

Methods: Male 6-week-old BALB/c mice were randomly assigned to one of the following groups: control (saline-treated, i.p.), CORM-2 only (30 mg/kg, i.p., four doses), cisplatin only (20 mg/kg, i.p., one dose), and CORM-2 + cisplatin, to determine whether cisplatin-based hearing impairment was alleviated by CORM-2 treatment.

Results: Our results revealed CORM-2 significantly attenuated cisplatin-induced hearing loss in young adult mice. CORM-2 co-treatment significantly decreased platinum accumulation in the inner ear and activated the plasma membrane repair system of the stria vascularis. Moreover, CORM-2 co-treatment significantly decreased cisplatin-induced inflammation, apoptosis, and cochlear necroptosis. Because the stria vascularis is the likely cochlear entry point of cisplatin, we next focused on the microvasculature. Cisplatin induced increased extravasation of a chromatic tracer (fluorescein isothiocyanate [FITC]-dextran, MW 75 kDa) around the cochlear microvessels at 4 days post-treatment; this extravasation was completely inhibited by CORM-2 co-therapy. CORM-2 co-treatment effectively maintained the integrity of stria vascularis components including endothelial cells, pericytes, and perivascular-resident macrophage-type melanocytes.

Conclusion: CORM-2 co-therapy substantially protects against cisplatin-induced ototoxicity by reducing platinum accumulation and toxic cellular stress responses. These data indicate that CORM-2 co-treatment may be translated into clinical strategy to reduce cisplatin-induced hearing loss.

Keywords: Apoptosis; CHMP4B; CORM-2; Carbon monoxide (CO)-releasing tricarbonyldichlororuthenium (II) dimer; Cisplatin; Endosomal sorting complexes required for transport (ESCRT); Hearing loss; Necroptosis; Ototoxicity; Plasma membrane repair.