A New Mechanism of Chemotherapy-Induced Painful Peripheral Neuropathy
Many chemotherapeutic drugs that kill cancer cells also damage the peripheral nervous system, resulting in chemotherapy-induced painful peripheral neuropathy (CIPN)—a condition that can last for weeks, months, or even years after cancer treatment has ceased. Now, in a rodent study, Daniela Salvemini, Saint Louis University School of Medicine, US, and colleagues show that one such chemotherapeutic agent, bortezomib, results in increased production of sphingolipids—fatty molecules associated with inflammation and neurodegenerative disease—in spinal cord astrocytes, contributing to CIPN.
They also demonstrate that fingolimod, a US Food and Drug Administration (FDA)-approved drug for multiple sclerosis that antagonizes sphingolipid signaling, could block and reverse CIPN in rats. This offers hope that the current findings could be translated quickly to help patients with CIPN.
Annemieke Kavelaars, University of Texas MD Anderson Cancer Center, Houston, US, whose own laboratory is looking for novel targets to treat CIPN but was not involved with the current study, said the results are “very promising.”
“We really need options to prevent and reverse CIPN—it’s a really big problem in cancer treatment—and there are no real treatments for it,” she said. “This paper not only looks into how CIPN is caused by bortezomib, but also suggests there are interventions that can both enhance the anti-cancer effects of chemotherapy drugs while protecting the nervous system from unnecessary damage.”
The research was published May 7 in the Journal of Experimental Medicine. A commentary on the paper by Edward Emery and John Wood, University College London, UK, appeared August 2 in the New England of Journal of Medicine.
The yin and yang of sphingolipid metabolism
According to the American Cancer Society, approximately 30 percent of cancer survivors experience CIPN. While the oncology field has become better and better at developing treatments to manage cancer, the peripheral nervous system is too often collateral damage. Salvemini said this a serious concern for cancer treatment, but it’s been difficult to understand how chemotherapeutic drugs produce CIPN.
“This is a condition that can limit the effective use of a number of chemotherapeutics. And with so many people now surviving for a long time after cancer treatment, we see people who will be living with this painful condition for long periods of time, and we have no way to treat them,” according to Salvemini. “There have been a number of mechanisms proposed for how these drugs lead to CIPN, as well as for how the peripheral and central nervous system may be impacted depending on the drug. But many studies now clearly highlight that changes within the dorsal horn of the spinal cord play an important role.”
To better understand what those changes might entail, Salvemini, along with first author Katherine Stockstill, also at Saint Louis School of Medicine, looked at how bortezomib, a chemotherapeutic drug commonly used in multiple myeloma and other cancers, affects sphingolipid metabolism, including through the release of a powerful pro-apoptotic mediator, called ceramide, in the sphingolipid pathway.
“Major chemotherapeutic agents kill cancer cells by making ceramide, and then ceramide kills the cancer cells,” Salvemini explained. “A downstream metabolite of ceramide is sphingosine-1-phosphate (S1P). There is a yin and yang between ceramide and S1P. Ceramide kills cancer cells, and S1P allows them to survive. And we’ve demonstrated previously that S1P causes pain by activating a receptor called S1PR1 (Finley et al., 2013; Janes et al., 2014; and see PRF related news). We wondered if we could inhibit the development of CIPN if we could selectively block the S1PR1 receptor.”
Uncovering the mechanisms of bortezomib-induced neuropathic pain
Salvemini and colleagues used both genetic and pharmacologic techniques to test their idea. First, the researchers used liquid chromatography-mass spectrometry to look at sphingolipid metabolism in the rat dorsal horn spinal cord and compared tissue from bortezomib-treated animals to those receiving saline. Rats treated with the chemotherapeutic agent showed both mechanical allodynia and mechanical hyperalgesia. Those rats also showed increased production of ceramide as well as its metabolites, including S1P, sphingosine, and dihydro-S1P (DH-S1P). This led to dysregulation of sphingolipid metabolism, which previous studies have linked to the development of pain.
Next, the group looked at the role of S1PR1, a receptor for which S1P and DH-S1P have strong affinities. First, the researchers inhibited S1PR1 using a selective antagonist called NIBR14. As expected, this ameliorated pain behaviors in the rats. The researchers saw similar results using a short interfering RNA that targets S1PR1, which significantly reduced the amount of S1PR1 protein in the dorsal horn. Other S1PR1-targeting drugs, including the functional S1PR1 antagonists ponesimod and fingolimod, which cause irreversible downregulation of S1PR1, prevented rats from developing neuropathic pain for 20 days after bortezomib treatment.
The investigators then looked to genetically modified mice with reduced levels of, or removal of, S1PR1 protein from spinal cord astrocytes; these cells have been implicated in neuroinflammation, and contain much higher amounts of S1PR1 than microglia and neurons. The researchers found that they could prevent or delay neuropathic pain in these animals after bortezomib treatment, compared to littermate controls.
“If you remove the S1PR1 receptor from the astrocytes in these mutant mice, CIPN does not occur,” said Salvemini. “We now see that S1PR1 activation in the astrocyte is critical to inducing and maintaining the neuropathic pain associated with bortezomib.”
When the researchers blocked S1PR1 with antagonist drugs like NIBR14 in mice, they saw fewer activated astrocytes, as well as decreased production of inflammatory cytokines, in the spinal cord. And electrophysiological experiments revealed increased glutaminergic signaling after bortezomib treatment, which was decreased after treatment with fingolimod.
Paving the way for a future treatment in people?
While Salvemini was happy to elucidate the pathways that contribute to CIPN, she wanted to find a way to reverse it. To that end, she and her colleagues then targeted rats, after 25 days of bortezomib-induced neuropathic pain, with infusions of ponesimod, NIBR14, or fingolimod. All three compounds over a six-day treatment completely reversed the pain in the animals.
“We now have strong evidence that fingolimod can both inhibit development of and reverse established pain,” said Salvemini. “We know that targeting S1PR1 receptors will not interfere with the anti-cancer mechanisms of chemotherapeutics, so we are in a strong position to do a clinical trial to see whether fingolimod can help treat CIPN in human patients.”
Kavelaars agrees. “This work not only adds to our understanding of the mechanisms involved with CIPN, but it also offers the possibility of a clinical trial and future treatment.”
Kayt Sukel is a freelance writer based outside Houston, Texas.
Image credit: Sherry Yates Young/123RF Stock Photo.
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