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Updated: Dec 30, 2025
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment
Wei Wang1,2, Muthu K Shanmugam1, Ping Xiang1
1Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore, Singapore.
Abstract:
Ototoxicity is a major adverse effect of platinum-based chemotherapeutics and currently, there remains a lack of United States Food and Drug Administration-approved therapies to prevent or treat this problem. In our study, we examined the role of the sphingosine 1-phosphate receptor 2 (S1P2) in attenuating cisplatin-induced ototoxicity in several different animal models and cell lines. We found that ototoxicity in S1P2 knockout mice is dependent on reactive oxygen species (ROS) production and that S1P2 receptor activation with a specific agonist, CYM-5478, significantly attenuates cisplatin-induced defects, including hair cell degeneration in zebrafish and prolonged auditory brainstem response latency in rats. We also evaluated the cytoprotective effect of CYM-5478 across different cell lines and showed that CYM-5478 protects neural-derived cell lines but not breast cancer cells against cisplatin toxicity. We show that this selective protection of CYM-5478 is due to its differential effects on key regulators of apoptosis between neural cells and breast cancer cells. Overall, our study suggests that targeting the S1P2 receptor represents a promising therapeutic approach for the treatment of cisplatin-induced ototoxicity in cancer patients.
Insights
Targeting the sphingosine 1-phosphate receptor 2 (S1P2) shows promise for preventing chemotherapy-induced ototoxicity. Activating S1P2 with CYM-5478 protects against cisplatin-induced hearing damage in preclinical models.
Area of Science:
- Ototoxicity and Cancer Therapeutics
- Pharmacology and Drug Development
Background:
- Platinum-based chemotherapies can cause ototoxicity, a significant side effect with no FDA-approved preventative or treatment therapies.
- Reactive oxygen species (ROS) play a role in chemotherapy-induced ototoxicity.
Purpose of the Study:
- To investigate the role of the sphingosine 1-phosphate receptor 2 (S1P2) in mitigating cisplatin-induced ototoxicity.
- To evaluate the therapeutic potential of S1P2 receptor activation for preventing hearing loss associated with chemotherapy.
Main Methods:
- Utilized S1P2 knockout mice and various cell lines to study ototoxicity mechanisms.
- Administered a specific S1P2 agonist, CYM-5478, to animal models (zebrafish, rats) and cell lines.
- Assessed cisplatin-induced ototoxicity through hair cell degeneration and auditory brainstem response latency.
- Examined the differential cytoprotective effects of CYM-5478 on neural and cancer cell lines.
Main Results:
- Ototoxicity in S1P2 knockout mice was found to be dependent on ROS production.
- S1P2 receptor activation with CYM-5478 significantly reduced cisplatin-induced hair cell degeneration in zebrafish.
- CYM-5478 treatment attenuated prolonged auditory brainstem response latency in rats exposed to cisplatin.
- CYM-5478 demonstrated cytoprotective effects in neural-derived cell lines but not in breast cancer cells against cisplatin toxicity.
- Differential regulation of apoptosis by CYM-5478 in neural versus cancer cells explains the selective protection.
Conclusions:
- Targeting the S1P2 receptor is a potential therapeutic strategy for managing cisplatin-induced ototoxicity.
- S1P2 activation may offer a protective mechanism against chemotherapy-related hearing damage in cancer patients.
