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

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Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
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Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
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Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
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Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
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Department of Biology, San Diego State University, San Diego, CA 92182, USA
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Authors to whom correspondence should be addressed.
Cancers 2020, 12(1), 211; https://doi.org/10.3390/cancers12010211
Received: 16 October 2019 / Revised: 8 November 2019 / Accepted: 9 January 2020 / Published: 15 January 2020
(This article belongs to the Special Issue The Sphingolipid Pathway in Cancer)
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. View Full-Text
Keywords: cisplatin; ototoxicity; sphingosine 1-phosphate; hearing loss; reactive oxygen species; cochlea; acoustic startle response; auditory brainstem response; CYM-5478 cisplatin; ototoxicity; sphingosine 1-phosphate; hearing loss; reactive oxygen species; cochlea; acoustic startle response; auditory brainstem response; CYM-5478
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Wang, W.; Shanmugam, M.K.; Xiang, P.; Yam, T.Y.A.; Kumar, V.; Chew, W.S.; Chang, J.K.; Ali, M.Z.B.; Reolo, M.J.Y.; Peh, Y.X.; Abdul Karim, S.N.B.; Tan, A.Y.; Sanda, T.; Sethi, G.; Herr, D.R. Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment. Cancers 2020, 12, 211.

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