Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy

Wei Wang, Ping Xiang, Wee Siong Chew, Federico Torta, Aishwarya Bandla, Violeta Lopez, Wei Lun Seow, Brenda Wan Shing Lam, Jing Kai Chang, Peiyan Wong, Kanokporn Chayaburakul, Wei Yi Ong, Markus R. Wenk, Raghav Sundar, Deron R. Herr*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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 stressresponse proteins, includingATF3and 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.

Original languageEnglish
Pages (from-to)1143-1152
Number of pages10
JournalJournal of Biological Chemistry
Volume295
Issue number4
DOIs
Publication statusPublished - 24 Jan 2020
Externally publishedYes

Fingerprint

Dive into the research topics of 'Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy'. Together they form a unique fingerprint.

Cite this