NEW YORK (Reuters Health) – Bortezomib-induced neuropathic pain results from dysregulation of sphingolipid metabolism in the spinal cord, a discovery that opens the way to treatment with an existing drug, researchers say.
Bortezomib, widely used to treat multiple myeloma and mantle cell non-Hodgkin lymphoma, causes peripheral neuropathy in more than 40% of patients. The mechanism behind this painful condition is poorly understood.
Part of bortezomib’s anticancer activity results from activation of the sphingolipid biosynthesis pathway to produce the potent proapoptotic sphingolipid ceramide, which is ultimately metabolized to produce sphingosine-1-phosphate (S1P), a potent antiapoptotic sphingolipid.
Dr. Daniela Salvemini from Saint Louis University School of Medicine, in St. Louis, Missouri, and colleagues investigated the contribution of bortezomib-induced alterations in sphingolipid metabolism to the development of neuropathic pain.
Bortezomib exposure was associated with increased levels of sphingosine, S1P and dihydro-S1P (another metabolite of ceramide) in the dorsal horn of the spinal cord (DHSC), and these changes were associated with the development of neuropathic pain, the team found.
This dysregulation of sphingolipid metabolism was associated with increases in inflammatory cytokines (tumor necrosis factor and IL-1beta) and decreases in anti-inflammatory cytokines (IL-10 and IL-4), they report in the Journal of Experimental Medicine, online April 27.
S1P in the DHSC of bortezomib-treated rats enhanced glutamate release, which also contributes to neuropathic pain.
Existing S1P receptor 1 (S1PR1) antagonists decreased production of inflammatory cytokines, prevented reductions in anti-inflammatory cytokines, blocked glutamate release and reduced neuropathic pain.
Two of these S1PR1 antagonists include fingolimod, an immunomodulator approved for treating multiple sclerosis, and ponesimod, which is in advanced clinical trials for multiple sclerosis.
“In conclusion, by using a multidisciplinary approach, our studies provide new insight into the underlying S1PR1-driven mechanisms engaged during bortezomib-induced neuropathic pain and establish the foundation for proof-of-concept studies with S1PR1-targeted agents that are already in clinical use or advanced clinical trials for other indications,” the researchers note.
“Our studies provide a compelling case for the consideration of repurposing (fingolimod) as an adjuvant to bortezomib for the prevention and treatment of chemotherapy-related neurotoxicity to address an immense unmet medical need,” they add.
Dr. Salvemini did not respond to a request for comments.
SOURCE: https://bit.ly/2HNIMox
J Exp Med 2018.
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