Statins May Guard Hearing from Deafening Cancer Chemotherapy

Mouse Study Suggests Approach to Protect Cancer Patients’ Hearing

Tuesday, March 24, 2020

ear

The widely used chemotherapy drug cisplatin kills sensory cells in the inner ear that are crucial for hearing, but new IRP research in mice suggests statin medications might curb hearing loss in cancer patients receiving cisplatin therapy.

The internet is filled with lists of ‘life hacks’ that provide instructions on how to re-purpose common items, from turning glass jars into flower vases to using sticky notes to remove dust or crumbs from the crevices of a computer keyboard. On occasion, this kind of inventive spirit can be used to improve human health as well. IRP researchers have found evidence in mice that a statin medication originally created to lower cholesterol might also reduce hearing loss caused by a common cancer therapy.1

A platinum-based chemical called cisplatin is one of the most effective and widely used anti-cancer drugs in existence. Unfortunately, while this form of chemotherapy has saved millions of lives, it is toxic to the sensory cells of the inner ear, called hair cells, that are crucial for hearing. These cells cannot regenerate in humans, so their destruction leads to permanent hearing loss.

Scientists studying this phenomenon have long known that hair cells respond to potentially harmful conditions like toxins and loud noises by triggering a ‘stress response’ that includes increased production of protective molecules called heat shock proteins. It just so happens that the statin medications currently taken by more than 35 million Americans to lower high cholesterol and prevent heart attacks and strokes also have been found to boost levels of heat shock proteins in cells, prompting researchers to investigate whether statins might preserve hearing in cancer patients undergoing cisplatin therapy.

“Heat shock protein induction in response to cellular stress is one of the most ubiquitous, conserved stress responses in all of biology,” says the study’s first author, IRP staff scientist Katharine Fernandez, Au.D., Ph.D. “Yeast do this, plants do it, all kinds of cells generate these proteins. When they are induced, these proteins can promote cell survival under a wide variety of stresses.”

In the new study, the IRP team — led by the study’s senior author, IRP senior investigator Lisa Cunningham, Ph.D.  — administered two different hearing tests to mice before and after prolonged cisplatin treatment. One of these hearing tests directly measures the function of one of the ear’s two sets of sensory hair cells, known as outer hair cells. The other test, known as auditory brainstem response (ABR) threshold testing, involves playing a variety of tones of different pitches at progressively lower volumes inside the ear until a tone fails to produce electrical activity in a part of the brain involved in hearing. If a sound fails to activate this brain region in one mouse (or person) but does in another mouse, that suggests the first mouse has worse hearing than the second. The ABR test, which is painless, is also used to test hearing in human newborns and children.

Dr. Lisa Cunningham

Dr. Lisa Cunningham

Some of the mice were also given a statin called lovastatin before and during the cisplatin treatment period. The researchers found that cisplatin worsened the animals’ hearing as measured by both tests, but mice given both cisplatin and lovastatin experienced markedly less hearing loss than those given only cisplatin. Mice given a placebo or lovastatin alone did not show changes in hearing. Furthermore, lovastatin reduced the number of outer hair cells that the cisplatin treatment destroyed. Intriguingly, lovastatin was particularly protective of the animals’ ability to hear high- and medium-pitched sounds, the hearing range typically most impaired by cisplatin.

“The high- and medium-pitched frequencies are particularly important for human communication because this is where we get the clarity in our speech,” explains Dr. Fernandez. “For example, to make out some of the consonants that give clarity to words like ‘boat’ and ‘coat,’ you need to be able to hear the mid-to-high frequencies.”

The new study also offers some clues as to how statins might protect hair cells. Lovastatin did not prevent the harmful buildup of platinum in the inner ear that results from cisplatin treatment, but it did boost the production of two potentially protective heat shock proteins. However, the study did not investigate whether that increase in heat shock proteins is necessary for lovastatin to preserve hair cells.

That question of cause and effect will be explored by Dr. Cunningham’s team in future studies. The group is also planning a clinical trial testing whether a different statin reduces hearing loss in cancer patients receiving cisplatin therapy.

“We have tried a number of different approaches to this over quite an extended period of time,” says Dr. Cunningham. “Statins are cheap, they’re well-tolerated, they don’t reduce the therapeutic efficacy of cisplatin, and they’re FDA-approved. Our hope is that if studies show statins reduce cisplatin-induced hearing loss in humans, these medications could be rapidly translated into widespread clinical use to help many patients being treated for cancer.”

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References:

[1] Lovastatin protects against cisplatin-induced hearing loss in mice. Fernandez K, Spielbauer KK, Rusheen A, Wang L, Baker TG, Eyles S, Cunningham LL. Hear Res. 2020 Feb 6;389:107905. doi: 10.1016/j.heares.2020.107905.

Category: Science