Mild pain killer blocks action of key protein required for hearing

In continuation of my update on 'diflunisal'

A Rice University study has found that the aspirin-like drug diflunisal blocks the action of prestin, a key protein that is required for hearing.

The research, which is available online in the open-access journal PLOS ONE, stemmed from a 2015 Rice study that screened more than a half-dozen nonsteroidal anti-inflammatory drugs, or NSAIDs, for possible interactions with the protein prestin. Prestin is a highly specialized protein that drives the action of outer hair cells in the cochlea, an inner-ear organ that allows people and animals to hear.

"Taking too much aspirin can cause temporary deafness, and researchers discovered more than a decade ago that this happens because salicylate, one of the primary metabolites of aspirin, interferes with prestin," said study lead author Guillaume Duret, a research scientist in Rice's Department of Electrical and Computer Engineering. "Given the number of commonly used NSAIDs that operate in a similar way to aspirin, it seemed like a good idea to find out whether they also might inhibit prestin."

Duret said diflunisal was the only drug in the test that blocked the action of prestin. He said the findings suggest that the inhibition occurs by competing with chloride ions in prestin, a mechanism that is similar to what has been proposed for salicylate. The study also found that the dosage needed to induce a reaction was less than the aspirin dose required to induce a similar reaction.

Diflunisal is primarily prescribed as a mild pain killer and an anti-inflammatory for arthritis. But Duret said the findings come at an important time because the medical community is considering repurposing diflunisal as a possible treatment for both cancer and amyloid polyneuropathy.

"So far, it's been used in a pill form that is ingested, and the known side effects are for relatively small doses, like as if you were taking aspirin," Duret said. "For greater doses that are perhaps injected, the side effects may not yet be known."

He conducted the study's experiments in 2015 with two of the world's leading experts on prestin and outer hair cells, Rice bioengineer Rob Raphael and Baylor College of Medicine molecular biologist Fred Pereira.

Ancient anti-inflammatory drug salicylic acid has cancer-fighting properties: Diflunisal -- a cousin of aspirin -- blocks a key protein that causes tumor formation in leukemia

In a study published in eLife, the researchers found that both salicylic acid and diflunisal suppress two key proteins that help control gene expression throughout the body. These sister proteins, p300 and CREB-binding protein (CBP), are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth. By inhibiting p300 and CBP, salicylic acid and diflunisal block the activation of these proteins and prevent cellular damage caused by inflammation. This study provides the first concrete demonstration that both p300 and CBP can be targeted by drugs and may have important clinical implications.

"Salicylic acid is one of the oldest drugs on the planet, dating back to the Egyptians and the Greeks, but we're still discovering new things about it," said senior author Eric Verdin, MD, associate director of the Gladstone Institute of Virology and Immunology. "Uncovering this pathway of inflammation that salicylic acid acts upon opens up a host of new clinical possibilities for these drugs."

Earlier research conducted in the laboratory of co-author Stephen D. Nimer, MD, director of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and a collaborator of Verdin's, established a link between p300 and the leukemia-promoting protein AML1-ETO. In the current study, scientists at Gladstone and Sylvester worked together to test whether suppressing p300 with diflunisal would suppress leukemia growth in mice. As predicted, diflunisal stopped cancer progression and shrunk the tumors in the mouse model of leukemia.

"The ability to repurpose drugs that are already FDA-approved to be part of novel therapies for cancer patients is incredibly exciting," said Nimer. "We have conducted a clinical trial of salicylic acid in patients with hematologic cancers and found it to be safe. Thus, this collaborative effort to develop novel epigenetic therapies is an important next step in our journey to find more effective treatment for leukemia patients."

The scientists are now pursuing a clinical trial that will test the ability of salicylic acid to treat patients with leukemia as part of novel combination therapies. Other possible clinical applications for salicylic acid include other forms of cancer, type 2 diabetes, inflammatory diseases, and even neurodegenerative disorders, such as Alzheimer's disease. Prior Gladstone research showed that another drug containing salicylic acid prevented the accumulation of tau in neurons and protected against cognitive decline in a mouse model of dementia.