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

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.

Immunomodulatory sphingosine-1-phosphates as plasma biomarkers of Alzheimer’s disease and vascular cognitive impairment

“…In order to further elucidate the mechanisms underlying associations of S1P with inflammation, we followed up on the clinical observations with in vitro studies using S1P-induced gene expression of acute-phase cytokines in primary astrocytes and astroglial cell line U373-MG. Interestingly, for both S1P-inducible [54] IL-1β and IL-6, the effects on cytokine gene upregulation were higher for d18:1 than for d16:1 S1P. The differential potency of d16:1 vs. d18:1 S1P has previously been shown in cell-based assays [58,59]. Here, the relatively weak effects of d16:1 S1P on cytokine gene induction may account for the lack of correlations between d16:1 and cytokine levels in the clinical cohort (see Table 4).…”

“…One important research gap is the elucidation of the specific S1P receptor subtypes mediating the immunomodulatory effects of d16:1 and d18:1 S1P. Previous work by others has suggested the potential involvement of S1PR 2 and S1PR 3 [42,60], while we have shown recently that d16:1 S1P has a lower potency for S1PR 2 and a lower efficacy for S1PR 3 [58]. Increasing d16:1 S1P concentrations would result in a reduction of pro-inflammatory S1PR 3 signaling, while having an additive effect on S1PR 1 and a minimal effect on S1PR 2 , thus indicating that the partial agonist effects of d16:1 S1P are receptor isoform-dependent.…”

Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

“…The knowledge of S1PR2-3-4 functions is still rudimentary and, so far, selective modulators of these receptors have been poorly investigated in vivo (Table 1). Among them, the potent S1PR2 agonist CYM-5478 has recently been examined in vivo in the context of pain [34] (discussed later). The S1PR2 antagonist, AB1, shows remarkable antitumor activity and exhibits a good efficacy, potency, and stability in vivo, but more studies are necessary to better define its selectivity [35].…”

Recent advances in the role of sphingosine 1‐phosphate in cancer

“…A similar phenomenon occurs in tumour explants from prostate cancer patients where poor survival is correlated with increased SK1 expression and tumour Gleason grade [58]. However, S1P 2 agonists might be useful in the management of chemotherapy-induced neuropathy since the selective S1P 2 agonist, CYM-5478, reduces allodynia in cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia via the transcription factor ATF3 and haeme oxygenase 1 (HO-1) [59].…”