TY - JOUR
T1 - Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy
AU - Wang, Wei
AU - Xiang, Ping
AU - Chew, Wee Siong
AU - Torta, Federico
AU - Bandla, Aishwarya
AU - Lopez, Violeta
AU - Seow, Wei Lun
AU - Lam, Brenda Wan Shing
AU - Chang, Jing Kai
AU - Wong, Peiyan
AU - Chayaburakul, Kanokporn
AU - Ong, Wei Yi
AU - Wenk, Markus R.
AU - Sundar, Raghav
AU - Herr, Deron R.
N1 - Publisher Copyright:
© 2020 Wang et al.
PY - 2020/1/24
Y1 - 2020/1/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078558457&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA119.011699
DO - 10.1074/jbc.RA119.011699
M3 - Article
C2 - 31882542
AN - SCOPUS:85078558457
SN - 0021-9258
VL - 295
SP - 1143
EP - 1152
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 4
ER -