The study was
published in the Journal of Experimental Medicine.
‘Fingolimod, a multiple sclerosis drug can negate the peripheral neuropathic pain caused by the cancer drug bortezomib this discovery can rapidly be translated to the clinic to prevent and treat the side effect.’
cancer treatment or chemotherapy
with anti-cancer drugs, many
patients experience a common, painful side effect known as chemotherapy-induced
peripheral neuropathy (CIPN)
problem is a major unmet clinical need because the increased efficacy of cancer
therapy has resulted in nearly 14 million cancer survivors in the United
States, many suffering from the long-term side effects of CIPN," says
Daniela Salvemini, Professor of Pharmacology and Physiology at the Saint Louis
University School of Medicine.
is a drug used to treat multiple
myeloma and mantle cell non-Hodgkin's lymphoma. The drug causes chronic,
distal, and symmetrical sensory peripheral neuropathy
is often accompanied with CIPN in over 40% of cancer patients, lasting even for
years after treatment. CIPN interferes with effective cancer treatment making
patients terminate chemotherapy and also affects the quality of life (QOL). The
reason why Bortezomib causes CIPN has been unknown.
Mechanism of Bortezomib causing CIPN
Sphingolipids are a class of molecules that have
previously been linked to neuropathic pain. In the current study,
Salvemini and colleagues found that bortezomib treated rats accelerated the
production of sphingolipids and causing accumulation of two sphingolipid
metabolites (sphingosine 1-phosphate and dihydrosphingosine 1-phosphate) in
their spinal cords showing signs of neuropathic pain. However, if the
production of the sphingolipids were blocked, the rats did not develop CIPN even
when they received bortezomib.
discovered that the two metabolites cause CIPN by activating a cell surface sphingolipid metabolite receptor protein called
S1PR1 on the surface of specialized central nervous system support cells called
astrocytes. Spinal cords of rats treated with bortezomib increased numbers of
astrocytes that cause neuropathic pain.
Another method to
prevent the rats from developing CIPN in response to bortezomib is to use drugs
that inhibit S1PR1.
an orally administered drug approved
to treat multiple sclerosis is one such inhibitor of S1PR1. Fingolimod does not
interfere with the ability of bortezomib to kill myeloma cells and has the
added advantage of working independently to inhibit tumor growth and thus
enhance the effects of bortezomib.
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," Salvemini says.
- Katherine Stockstill, Timothy M. Doyle, Xisheng Yan, Zhoumou Chen, Kali Janes, Joshua W.Little, Kathryn Braden, Filomena Lauro, Luigino Antonio Giancotti, Caron Mitsue Harada, RuchiYadav, Wen Hua Xiao, Jack M. Lionberger, William L. Neumann, Gary J. Bennett, Han-RongWeng, Sarah Spiegel, Daniela Salvemini "Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain" Journal of Experimental Medicine Apr (2018), jem.20170584; DOI: 10.1084/jem.20170584