Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment
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 (S1P<sub>...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/1/211 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wei Wang |
| collection | DOAJ |
| description | 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 (S1P<sub>2</sub>) in attenuating cisplatin-induced ototoxicity in several different animal models and cell lines. We found that ototoxicity in S1P<sub>2</sub> knockout mice is dependent on reactive oxygen species (ROS) production and that S1P<sub>2</sub> 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 S1P<sub>2</sub> receptor represents a promising therapeutic approach for the treatment of cisplatin-induced ototoxicity in cancer patients. |
| first_indexed | 2024-03-12T06:00:04Z |
| format | Article |
| id | doaj.art-e6c34148f2cf484ab26baa8929821169 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:00:04Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e6c34148f2cf484ab26baa89298211692023-09-03T04:12:29ZengMDPI AGCancers2072-66942020-01-0112121110.3390/cancers12010211cancers12010211Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin TreatmentWei Wang0Muthu K. Shanmugam1Ping Xiang2Ting Yu Amelia Yam3Vineet Kumar4Wee Siong Chew5Jing Kai Chang6Muhammad Zulfaqar Bin Ali7Marie J. Y. Reolo8Yee Xin Peh9Siti Nasuha Binte Abdul Karim10Andrew Y.Y. Tan11Takaomi Sanda12Gautam Sethi13Deron R. Herr14Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeCancer Science Institute of Singapore, National University of Singapore, Singapore 117599, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, SingaporeDepartment of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, SingaporeOtotoxicity 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 (S1P<sub>2</sub>) in attenuating cisplatin-induced ototoxicity in several different animal models and cell lines. We found that ototoxicity in S1P<sub>2</sub> knockout mice is dependent on reactive oxygen species (ROS) production and that S1P<sub>2</sub> 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 S1P<sub>2</sub> receptor represents a promising therapeutic approach for the treatment of cisplatin-induced ototoxicity in cancer patients.https://www.mdpi.com/2072-6694/12/1/211cisplatinototoxicitysphingosine 1-phosphatehearing lossreactive oxygen speciescochleaacoustic startle responseauditory brainstem responsecym-5478 |
| spellingShingle | 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 Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment Cancers cisplatin ototoxicity sphingosine 1-phosphate hearing loss reactive oxygen species cochlea acoustic startle response auditory brainstem response cym-5478 |
| title | Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment |
| title_full | Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment |
| title_fullStr | Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment |
| title_full_unstemmed | Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment |
| title_short | Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment |
| title_sort | sphingosine 1 phosphate receptor 2 induces otoprotective responses to cisplatin treatment |
| topic | cisplatin ototoxicity sphingosine 1-phosphate hearing loss reactive oxygen species cochlea acoustic startle response auditory brainstem response cym-5478 |
| url | https://www.mdpi.com/2072-6694/12/1/211 |
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