Journal of Biological Chemistry
Volume 295, Issue 4, 24 January 2020, Pages 1143-1152
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Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy

https://doi.org/10.1016/S0021-9258(17)49922-4Get rights and content
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Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1–5. In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2. We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.

neuroprotection
pharmacology
sphingosine 1-phosphate (S1P)
G-protein–coupled receptor
glial cell
cancer
anticancer drug
chemotherapy
cisplatin
glial satellite cells
neuropathy
oxaliplatin

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This work was supported by the Ministry of Education, Singapore, Grant T1-2013Sep-09 (to D. R. H.), by National University Health System Grants NUHSRO/2014/085/AF-Partner/01 (to D. R. H.) and NUHSRO/2017/064/Bridging/02 (to D. R. H.), and by National Medical Research Council, Grant NMRC/CG/M009/2017_NUH/NUHS (to P. W.). The authors declare that they have no conflicts of interest with the contents of this article.

This article was selected as one of our Editors' Picks.

This article contains Figs. S1 and S2 and Table S1.

Edited by Dennis R. Voelker

1

Both authors contributed equally to this work.