Working with cells in test tubes and in mice, researchers discovered that a chemical commonly used as a dog food preservative prevents chemotherapy-associated peripheral neuropathy. Four of every five patients with cancer receiving chemotherapy with paclitaxel experience the painful condition.
Ethoxyquin is an antioxidant that is approved by the FDA as a preservative. Experiments found that it binds certain cell proteins in a way that limits their exposure to the damaging effects of paclitaxel. The research was published in Annals of Neurology (2013; doi:10.1002/ana.24004).
The research team hopes to build on the protective effects of ethoxyquin’s chemistry to develop a drug cancer patients could take before administration of paclitaxel, much like antinausea medication is given to stave off nausea. Although approximately half of patients recover from paclitaxel-induced peripheral neuropathy, many continue to experience pain, numbness, and tingling that is often debilitating for the rest of their lives.
“Millions of people with breast cancer, ovarian cancer, and other solid tumors [receive] paclitaxel to treat their cancer and 80% of them will [develop] peripheral neuropathy as a result,” said study author Ahmet Höke, MD, PhD, a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and director of the Neuromuscular Division in Baltimore, Maryland. “They’re living longer thanks to the chemotherapy, but they are often miserable. Our goal is to prevent [the] neuropathy in the first place.”
Höke and his team knew from previous experiments that adding paclitaxel to a nerve cell line growing in a petri dish would cause neurodegeneration. In a series of experiments, Höke’s team added paclitaxel to nerve cells, along with some 2,000 chemicals—one at a time—to see which, if any, could interrupt the degenerative process. Ethoxyquin did, apparently by making the cells resistant to the toxic effects of paclitaxel.
Once the researchers identified ethoxyquin’s effects, they gave intravenous paclitaxel to mice, and saw nerves in their paws degenerate in a couple of weeks. But when they gave the mice ethoxyquin at the same time as the paclitaxel, it prevented two-thirds of the nerve degeneration. Höke said this would have a big impact on quality of life if the same effects were to occur in humans.
Specifically, Höke and his team discovered that ethoxyquin molecules were binding to Hsp90, one of the so-called heat shock proteins that cells defensively make more of whenever they are stressed. Hsp90 acts as a cell’s quality control officer, determining whether a protein is properly formed before sending it out where it is needed. Two other proteins, ataxin-2 and Sf3b2, cannot bind to Hsp90 when ethoxyquin binds to Hsp90. When ataxin-2 and Sf3b2 cannot bind to the cell, it senses that the proteins are flawed, the proteins are degraded, and their levels in the cell diminished.