2. Academic Validation
  3. Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy

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

  • J Biol Chem. 2020 Jan 24;295(4):1143-1152. doi: 10.1074/jbc.RA119.011699.
Wei Wang 1,  Ping Xiang 1,  Wee Siong Chew 1,  Federico Torta 2 3,  Aishwarya Bandla 4,  Violeta Lopez 5,  Wei Lun Seow 1,  Brenda Wan Shing Lam 1,  Jing Kai Chang 1,  Peiyan Wong 6,  Kanokporn Chayaburakul 7,  Wei-Yi Ong 8 9,  Markus R Wenk 2 3,  Raghav Sundar 10 11 12,  Deron R Herr 13 14
Affiliations

Affiliations

  • 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
  • 2 Singapore Lipidomics Incubator (SLING), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
  • 3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
  • 4 The N.1 Institute for Health, National University of Singapore, Singapore 119077.
  • 5 Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
  • 6 Neuroscience Phenotyping Core, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
  • 7 Anatomy Unit, Faculty of Science, Rangsit University, Pathum Thani 12000, Thailand.
  • 8 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
  • 9 Neurobiology and Ageing Research Programme, National University of Singapore, Singapore 119077.
  • 10 The N.1 Institute for Health, National University of Singapore, Singapore 119077 raghav_sundar@nuhs.edu.sg.
  • 11 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
  • 12 Department of Haematology-Oncology, National University Health System, Singapore 119074.
  • 13 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228 phcdrh@nus.edu.sg.
  • 14 Department of Biology, San Diego State University, San Diego, California 92182.
PMID: 31882542 DOI: 10.1074/jbc.RA119.011699
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 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.

Keywords

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

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