An additive that keeps dog food fresh may prevent a common cancer drug’s painful side effect.
The Food and Drug Administration-approved preservative, an antioxidant called ethoxyquin, binds to certain cell proteins in a way that limits their exposure to the damaging effects of the chemotherapy drug, new research has found.
Four of five Taxol users suffer from hand and feet pain, known as peripheral neuropathy. While half recover, the other half continues to have often-debilitating pain, numbness, and tingling for the rest of their lives.
“Millions of people with breast cancer, ovarian cancer, and other solid tumors get Taxol to treat their cancer and 80 percent of them will get peripheral neuropathy as a result,” says Ahmet Höke, professor of neurology and neuroscience at the Johns Hopkins University School of Medicine.
“They’re living longer thanks to the chemotherapy, but they are often miserable. Our goal is to prevent them from getting neuropathy in the first place.”
1 in 2,000
Höke’s experiments, published in the Annals of Neurology, were conducted in test tubes and with mice—the idea has not yet been tested in humans. But the hope, researchers say, is to build on the protective effect of ethoxyquin’s chemistry and develop a drug that could be given to cancer patients before they receive Taxol, also known by the generic name paclitaxel. The idea is much the same as using medication to stave off the nausea that is also a common chemotherapy side effect.
Höke and his team knew from previous experiments that adding Taxol to a nerve cell line growing in a petri dish would cause neurodegeneration. In a series of experiments, they hunted for compounds that might interrupt the degenerative process.
They added Taxol to nerve cells along with some 2,000 chemicals—one at a time—to see which, if any, could do that. Ethoxyquin did so, Höke says, apparently by making the cells resistant to the toxic effects of the Taxol.
Once they identified ethoxyquin’s effects, they gave intravenous Taxol to mice, and saw nerves in their paws degenerate in a couple of weeks. But when they gave ethoxyquin to the mice at the same time as the Taxol, it prevented two-thirds of the nerve degeneration. Höke says that would have a big impact on quality of life if the same effects were to occur in humans.
Sparing the nerves
Specifically, Höke and his team discovered that molecules of ethoxyquin 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. When ethoxyquin binds to Hsp90, two other proteins—ataxin-2 and Sf3b2—can’t bind to Hsp90. When they can’t bind, the cell senses that these two proteins are flawed, so they are degraded and their levels in the cell diminished.
Höke says his team is not certain why too much of those two proteins appears to have a negative effect on nerves, but reducing their levels clearly appears in their studies to make cells more resistant to Taxol toxicity.
‘Huge public health issue’
Höke and his colleagues are looking into whether this medication could also make nerves more resistant to damage in peripheral neuropathy caused by HIV and diabetes, two other major causes of the pain.
A previous study, Höke says, showed that ataxin-2 may cause degeneration in motor neurons in a rare form of ALS, commonly known as Lou Gehrig’s disease, suggesting that ethoxyquin or some version of it might also benefit people with this disorder.
Twenty to 30 million Americans suffer from peripheral neuropathy. Höke says it’s a “huge public health issue” that doesn’t get much attention because it is not fatal.
Höke’s team is hoping to conduct safety studies with ethoxyquin in animals in advance of possible testing in people. He says that while too much ethoxyquin is thought to be potentially harmful to dogs, the needed dose for humans would likely be 20-to-30-fold lower than what is found in dog food.
Ethoxyquin was developed in the 1950s as an antioxidant, a compound to prevent pears and other foods from becoming discolored and spoiling.
The Foundation for Peripheral Neuropathy, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the National Institute of Neurological Disorders and Stroke, and the Johns Hopkins Brain Science Institute funded the research.
Source: Johns Hopkins University