In:
Journal of Biological Chemistry, Elsevier BV, Vol. 295, No. 4 ( 2020-01-24), p. 1143-1152
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: S1P 1–5 . 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 S1P 2 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 S1P 1 signaling, shifting the balance away from S1P 2 . We further show that a selective S1P 2 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 S1P 2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.
Type of Medium:
Online Resource
ISSN:
0021-9258
,
1083-351X
DOI:
10.1074/jbc.RA119.011699
Language:
English
Publisher:
Elsevier BV
Publication Date:
2020
detail.hit.zdb_id:
2141744-1
detail.hit.zdb_id:
1474604-9
SSG:
12
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