Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment

• Main Authors: Wei Wang, Muthu K. Shanmugam, Ping Xiang, Ting Yu Amelia Yam, Vineet Kumar, Wee Siong Chew, Jing Kai Chang, Muhammad Zulfaqar Bin Ali, Marie J. Y. Reolo, Yee Xin Peh, Siti Nasuha Binte Abdul Karim, Andrew Y.Y. Tan, Takaomi Sanda, Gautam Sethi, Deron R. Herr
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Cancers
• Subjects: cisplatin; ototoxicity; sphingosine 1-phosphate; hearing loss; reactive oxygen species; cochlea; acoustic startle response; auditory brainstem response; cym-5478
• Online Access: https://www.mdpi.com/2072-6694/12/1/211

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.