Understanding how aspirin reduces inflammation could lead to alternatives with fewer side effects.

New research has revealed important information about how aspirin works. Even though this drug has been commercially available since the late 1800s, scientists have yet to fully elucidate its detailed mechanism of action and cellular targets. The new findings could pave the way for safer alternatives to aspirin and may also have implications for improving cancer immunotherapies.

Aspirin, which is a non-steroidal anti-inflammatory drug, is one of the most widely used drugs in the world. It is used to treat pain, fever, and inflammation, and about 29 million people in the United States take it daily to reduce the risk of cardiovascular disease.

Scientists know that aspirin inhibits the enzyme cyclooxygenase, or COX, which creates messenger molecules essential to the inflammatory response. Researchers led by Subhrangsu Mandal, professor of chemistry and biochemistry at the University of Texas at Arlington, have discovered more about this process.

Researchers have made new discoveries about the mechanism of action and cellular targets of aspirin. Their results suggest a potential interaction between the enzyme cyclooxygenase, or COX, and indoleamine dioxygenases, or IDOs, during inflammation. Credit: Subhrangsu Mandal, University of Texas at Arlington

Prarthana Guha, a graduate student in Mandal’s lab, presented the team’s findings at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, March 25-28 in Seattle. Avisankar Chini also made important contributions to the study.

“Aspirin is a magic drug, but its long-term use can cause harmful side effects such as internal bleeding and organ damage,” Mandal said. “It’s important that we understand how it works so we can develop safer drugs with fewer side effects.”

The team found that aspirin controls transcription factors necessary for cytokine expression during inflammation while also influencing many other inflammatory proteins and non-coding RNAs that are closely linked to inflammation and response. immune. Mandal said this work required a unique interdisciplinary team with expertise in inflammation signaling biology and organic chemistry.

They also showed that aspirin slows the breakdown of amino acids

” data-gt-translate-attributes=”[{” attribute=””>acid tryptophan into its metabolite kynurenine by inhibiting associated enzymes called indoleamine dioxygenases, or IDOs. Tryptophan metabolism plays a central role in the inflammation and immune response.

“We found that aspirin downregulates IDO1 expression and associated kynurenine production during inflammation,” Mandal said. “Since aspirin is a COX inhibitor, this suggests potential interplay between COX and IDO1 during inflammation.”

IDO1 is an important target for immunotherapy, a type of cancer treatment that helps the body’s immune system seek out and destroy cancer cells. Because COX inhibitors modulate the COX–IDO1 axis during inflammation, the researchers predict that COX inhibitors might also be useful as drugs for immunotherapy.

Mandal and his team are now creating a series of small molecules that modulate COX–IDO1 and will explore their potential use as anti-inflammatory drugs and immunotherapeutic agents.

Meeting: Discover BMB

Research in Mandal’s lab is funded by National Institute of Health grant R15 HL142032-01.