Anti-sedatives may ease side effects of cancer therapy

Researchers in China have found that inhibiting a protein called GABAA receptor can protect gut stem cells from the toxic effects of chemotherapy and radiotherapy. The study, published Sept. 20 in the Journal of Experimental Medicine (JEM), suggests that the FDA-approved anti-sedative drug flumazenil, which targets GABAA receptors, can alleviate some of the common gastrointestinal side effects, such as diarrhea and vomiting, caused by many cancer treatments.

Because they have to constantly multiply and replace the cells lining the intestinal wall, intestinal stem cells are very sensitive to chemotherapy and radiotherapy. These treatments damage the DNA of gut stem cells and cause them to die, leading to gut damage and a variety of painful gastrointestinal symptoms. These toxic side effects, which can persist long after treatment has ended, limit the drug or radiation dose that can be given to cancer patients and worsen their quality of life.

A research team led by Dawei Chen and Jingxin Li at Cheeloo College of Medicine, Shandong University, found that levels of a protein called GABRA1 increase in the gut stem cells of mice treated with radiation or a chemotherapy drug. GABRA1 is part of the GABAA receptor, which is best known for its role in the nervous system, where it binds to the neurotransmitter g-aminobutyric acid (GABA). But GABA and the GABAA receptor are also present in other tissues throughout the body.

The researchers found that inhibiting the GABAA receptor protected mice from the toxic side effects of chemotherapy or radiotherapy, reducing the amount of DNA damage and increasing gut stem cell survival. This allowed the mice to maintain a normal gut wall and survive lethal doses of radiation or chemotherapy.

Chen and colleagues found that inhibiting the GABAA receptor protects gut stem cells from DNA damage by limiting the formation of free radicals in response to chemoradiotherapy. Crucially, however, the researchers determined that inhibiting the GABAA receptor does not prevent radiation or chemotherapy drugs from killing cancer cells.

Flumazenil is a cheap, GABAA receptor inhibitor approved by the U.S. Food and Drug Administration for the treatment of benzodiazepine overdoses and reverse anesthesia. Chen and colleagues found that flumazenil could also protect the gut of mice from the toxic effects of chemoradiotherapy. In addition, flumazenil also protected human colon organoids — miniature organs grown in the lab from human colon stem cells — against chemotherapy and radiation.

Taken together, our data suggest that inhibiting the GABAA receptor is a promising strategy to specifically protect the gut against chemoradiotherapy,” says Chen. “Future studies are needed to investigate the pharmacodynamics and tolerability of flumazenil in cancer patients treated in the clinic.”

Zhang et al. 2022. J. Exp. med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20220541?PR

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