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. Epub 2019 Dec 27.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / chemistry
  • Axons / pathology
  • Biomarkers / metabolism
  • Cisplatin / adverse effects
  • Female
  • Humans
  • Lysophospholipids / chemistry
  • Lysophospholipids / metabolism
  • Myelin Sheath / pathology
  • Neuroglia / pathology
  • PC12 Cells
  • Peripheral Nervous System Diseases / chemically induced*
  • Peripheral Nervous System Diseases / metabolism*
  • Peripheral Nervous System Diseases / pathology
  • Platinum / adverse effects
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Sphingosine / analogs & derivatives
  • Sphingosine / chemistry
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors / metabolism*


  • Antineoplastic Agents
  • Biomarkers
  • Lysophospholipids
  • S1PR2 protein, human
  • Sphingosine-1-Phosphate Receptors
  • sphingosine 1-phosphate
  • Platinum
  • Sphingosine
  • Cisplatin