A New Way to Prevent Nerve Damage Caused by Chemotherapy?

February 18, 2021

About 60% of cancer patients treated with chemotherapy develop painful nerve damage but no drugs exist to prevent this complication.

Now a new study—that identifies how one agent causes nerve degeneration—may lead to the development of the first drugs to prevent peripheral neuropathy and identify people who may be at greatest risk of developing the condition.

excess D2 (white) accumulates in neurons after treatment with bortezomib
D2 (white) accumulates on the microtubules of neurons after treatment with the chemotherapy agent bortezomib, leading to the degeneration of the neurons. Image credit: Maria Elena Pero and Francesca Bartolini, Columbia University.

“Peripheral neuropathy is a serious complication for patients, and chemotherapy is sometimes even halted to reduce the patient’s pain,” says the study’s senior author, Francesca Bartolini, PhD, associate professor of pathology & cell biology at Columbia University Vagelos College of Physicians and Surgeons. “We don’t have effective treatments to prevent neuropathy, mainly because we don’t know why chemotherapy leads to nerve pain.”

Bartolini and her colleagues found that the answer may lie in the way the chemotherapy drugs affect the nerve’s microtubules.

Modified microtubules

In the new study, the researchers discovered that bortezomib, a drug often used to treat multiple myeloma, leads to a greater accumulation of a microtubule modification called delta-2 tubulin, or D2 for short, in the sensory nerves of rats and humans treated with the drug.

Microtubules are the highways onto which organelles are distributed throughout the cell. Microtubules disintegrate and rebuild on a regular basis, but in nerve cells of animals treated with bortezomib, microtubules disintegrate less and start accumulating D2. 

The buildup of D2 leads to a defect in the transport of mitochondria, the powerhouse of the cell, causing the ends of the neurons to degenerate.

images of neurofilaments showing neuronal degeneration in those treated with bortezomib
Neurodegeneration caused by bortezomib. Untreated neurons in left image; bortezomib-treated neurons in right image. Photos from Francesca Bartolini.

New drug targets

The findings pave the way for the development of new drugs designed to treat chemo-induced neuropathy. 

“Small molecule inhibitors of the enzymes that generate D2 could slow D2 accumulation and the degeneration of nerves,” Bartolini says. “D2 detection could also serve as a biomarker of sensory nerve damage and determine who is at greatest risk for developing severe peripheral neuropathy.”

Drugs that reduce D2 accumulation may also work to prevent neuropathy induced by other chemotherapies. For instance, two other widely used chemotherapeutics, paclitaxel and vincristine, also affect microtubules and cause an increase in D2 in cultured cells. 

Although it’s not yet known if D2 accumulates in the sensory neurons of animals treated with these drugs, the new findings suggest that damage to tubulin may be a common theme in sensory impairment caused by several classes of anticancer drugs. 

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References

More information

The research appears in “Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy,” published Jan. 26 in Proceedings of the National Academy of Sciences.

Other authors: Maria Elena Pero (Columbia University), Cristina Meregalli (University of Milano-Bicocca), Xiaoyi Qu (Columbia), Grace Ji-eun Shin (Columbia), Atul Kumar (Columbia), Matthew Shorey (Penn State), Melissa M. Rolls (Penn State), Kurenai Tanji (Columbia), Thomas H. Brannagan (Columbia), Paola Alberti (University of Milano-Bicocca), Giulia Fumagalli (University of Milano-Bicocca), Laura Monza (University of Milano-Bicocca), Wesley B. Grueber (Columbia), and Guido Cavaletti (University of Milano-Bicocca).

The study was supported by the Thompson Family Foundation; the U.S. National Institutes of Health (grants RO1AG050658 and R21NS120076); and the Italian Ministero dell’Istruzione and Ministero dell’Università e della Ricerca (grant PRIN-2017FJC3-004).

A patent application related to this study is currently pending.