Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation.

Abstract

Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.

• Authors: Shaness A Grenald, Timothy M Doyle, Hong Zhang, Lauren M Slosky, Zhoumou Chen, Tally M Largent-Milnes, Sarah Spiegel, Todd W Vanderah, Daniela Salvemini
• Journal: Pain (Pain) Vol. 158 Issue 9 Pg. 1733-1742 (Sep 2017) ISSN: 1872-6623 [Electronic] United States
• PMID: 28570482 (Publication Type: Journal Article)

Chemical References

• Immunosuppressive Agents
• Receptors, Lysosphingolipid
• S1pr1 protein, mouse
• Sphingosine-1-Phosphate Receptors
• Sulfones
• TASP0277308
• Triazoles
• Interleukin-10
• Proprotein Convertases
• Serine Endopeptidases
• membrane-bound transcription factor peptidase, site 1
• Fingolimod Hydrochloride

Topics

• Animals
• Breast Neoplasms (complications, pathology)
• Cancer Pain (drug therapy, etiology, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Fingolimod Hydrochloride (pharmacology, therapeutic use)
• Gene Expression Regulation, Neoplastic (drug effects)
• Immunosuppressive Agents (pharmacology, therapeutic use)
• Interleukin-10 (metabolism)
• Mice
• Mice, Inbred C57BL
• Neurogenic Inflammation (drug therapy, etiology, metabolism)
• Proprotein Convertases (antagonists & inhibitors, metabolism)
• Receptors, Lysosphingolipid (antagonists & inhibitors, metabolism)
• Serine Endopeptidases (metabolism)
• Signal Transduction (drug effects)
• Sphingosine-1-Phosphate Receptors
• Spinal Cord (drug effects, metabolism)
• Sulfones (pharmacology, therapeutic use)
• Triazoles (pharmacology, therapeutic use)