Researchers pinpoint possible way to prevent permanent hearing loss caused by common childhood cancer drug

Scientists at the University of Alberta have identified a receptor in cells that could be the key to preventing permanent hearing loss in childhood cancer survivors treated with the drug cisplatin. The researchers think that by inhibiting the receptor, they can eliminate the drug’s toxic side effects that cause the hearing loss.

Cisplatin is an incredibly effective chemotherapeutic agent when it comes to treating solid tumors in children, contributing to an 80 percent survival rate, according to U of A researcher Amit Bhavsar, an assistant professor in the Department of Medical Microbiology and Immunology. in five years. The problem has always been with the side effects. Nearly 100 percent of patients who receive higher doses of cisplatin have some degree of permanent hearing loss. The ability to prevent this side effect would drastically improve the quality of life of childhood cancer survivors after they recover from the disease.

As Bhavsar explains, many researchers are looking at the harmful side effects of cisplatin from a genetic perspective, trying to determine underlying risk factors for hearing loss or how it works as a chemotherapy agent. Quite a bit was known about the progression of hearing loss as a side effect, but it was the first spark – the booster that got it all started – that remained a mystery.

Thinking outside the box, Bhavsar and his team went all the way back to the periodic table with their approach, getting some clues to the chemical makeup of cisplatin itself and eventually identifying a particular receptor that turned on.

The receptor in question is Toll-like receptor 4 (TLR4), which is involved in the body’s immune response. TLR4 works by crossing the cell membrane, extending part of itself outside the cell to sample the environment, and to look for various signals that indicate damage or some kind of danger.

“It is a receptor that your body normally uses to detect when there is a problem, such as an infection. This receptor turns on and starts producing these signals that tell the cell that it is under voltage. Unfortunately, in the case of cisplatin, those signals eventually lead to the death of the cells responsible for hearing. “

The cells affected by the signals from TLR4 are located in the cochlea of ​​the ear, where they play a vital role in hearing and translate vibrations in the ear into electrical impulses. Cisplatin also accumulates in the kidneys, but the difference is that it can be flushed out and diluted in that part of the body; in a closed system such as the ear, it accumulates and damages the cells.

‘These cells do not renew. You really only get one chance and when they’re gone you’re in trouble. The hearing loss is permanent, ”said Bhavsar.

The only way to prevent the damage is to stop the signals that TLR4 produces that lead to the accumulation of cisplatin. To confirm the efficacy of inhibiting the TLR4 receptor, Bhavsar and his team looked at zebrafish models, with the help of Ted Allison, an associate professor in the Department of Biological Sciences and a member of the U of A’s Neuroscience and Mental Health Institute. They examined neuromasts, sensory cells in zebrafish that behave in the same way as human hair cells that are typically damaged by cisplatin. Bhavsar was able to show that inhibition of TLR4 led to inhibition of the damage to the sensory cells.

/ Release from the University of Alberta. This material comes from the original organization and may be point-in-time in nature, edited for clarity, style and length. View full here.

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