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Bortezomib
Researchers say they’ve discovered why multiple myeloma (MM) patients may experience chemotherapy-induced peripheral neuropathy (CIPN) when treated with bortezomib.
The group’s study also suggests fingolimod—a drug approved to treat multiple sclerosis—could mitigate CIPN without compromising the efficacy of bortezomib.
Daniela Salvemini, PhD, of the Saint Louis University School of Medicine in St. Louis, Missouri, and her colleagues reported these findings in the Journal of Experimental Medicine.
The researchers said bortezomib causes CIPN in more than 40% of patients, but the reasons for this are unclear.
With their study, Dr Salvemini and her colleagues found that bortezomib accelerates the production of sphingolipids, which have been linked to neuropathic pain.
Rats treated with bortezomib began to accumulate 2 sphingolipid metabolites—sphingosine 1-phosphate and dihydrosphingosine 1-phosphate—in their spinal cords at the time they began to show signs of neuropathic pain.
Blocking the production of these molecules prevented the animals from developing CIPN in response to bortezomib.
Sphingosine 1-phosphate and dihydrosphingosine 1-phosphate can activate a cell surface receptor protein called S1PR1. Dr Salvemini and her colleagues determined that the 2 metabolites cause CIPN by activating S1PR1 on the surface of astrocytes, resulting in neuroinflammation and enhanced release of the excitatory neurotransmitter glutamate.
Drugs that inhibit S1PR1 prevented rats from developing CIPN in response to bortezomib. One such inhibitor was fingolimod, a drug approved by the US Food and Drug Administration (FDA) to treat multiple sclerosis.
In addition to preventing CIPN, fingolimod did not inhibit bortezomib’s ability to kill MM cells. In fact, fingolimod has demonstrated anticancer activity in past studies.
“Because fingolimod shows promising anticancer potential and is already FDA-approved, we think that our findings in rats can be rapidly translated to the clinic to prevent and treat bortezomib-induced neuropathic pain,” Dr Salvemini said.