Aspirin-Like Compounds Could Treat Numerous Human Diseases

People have used aspirin to treat pain, fever and inflammation for more than a century, and the drug is also used to reduce the risk of strokes, heart attacks and some cancers. An estimated 100 billion aspirin tablets are taken worldwide each year, but how it works is still only partially understood.

Dan Klessig, a faculty member at Boyce Thompson Institute, has long suspected that aspirin’s broad effects are due in part to its primary metabolite, salicylic acid (SA). He reached this conclusion because humans metabolize aspirin into SA within minutes, and for nearly 50 years synthetic SA was used to treat pain, fever and inflammation before the advent of aspirin.

Moreover, for millennia many cultures throughout the world have treated pain, fever and inflammation with SA-rich plants — such as willow, meadowsweet and poplar — and continue to do so today.

In order to find clues as to how the compound works, Klessig led a group of researchers to identify human proteins that bind to SA and have their activity altered as a result. The BTI team also created a detailed network that links the newly discovered SA-binding proteins to dozens of human diseases, such as Alzheimer’s disease, Type II diabetes and arthritis.

The results, published in Scientific Reports in September, offer drug and nutraceutical developers a roadmap with multiple avenues for future research on new targets of aspirin and SA, and on novel, more potent synthetic or natural plant-derived SA derivatives.

“There are more potent derivatives of SA that could be made, as well as some present in medicinal plants such as licorice, that have the potential to treat a host of diseases,” Klessig said. “I think there is such untapped wealth here.”

First author Hyong Woo Choi agrees. “Based on our current research, SA might have effects on several developmental, neurological, psychiatric, ophthalmological and muscular diseases, as well as on cancer,” he said.

Choi, currently an assistant professor in the Department of Plant Medicals at South Korea’s Andong National University, was a senior research associate in Klessig’s lab when the study was done.

The team’s research was an outgrowth of three decades of work by Klessig, beginning with his 1990 Science paper describing how plants produce SA to protect themselves from viral infections and other pathogens.

“All plants contain SA, and plant-based diets result in almost as much SA in the body as taking a baby aspirin each day,” says Klessig. “We evolved eating plants, so it’s not surprising that SA affects our physiology.”

To investigate how SA works in humans, Klessig and his team used a novel screen to identify about 2,000 human proteins that bind to the SA derivative 4azSA. The researchers partnered with Adrian Powell and Susan Strickler at the BTI Computational Biology Center (BCBC) to narrow the pool to 95 candidate SA-binding proteins (cSABPs), which were the most highly enriched in the screen. They fell into five broad physiological categories, including protein metabolism and immunity.

Two proteins, ENO1 and PKM2, topped the list. “These two proteins are important because they’re involved in the last two steps of glycolysis,” Klessig said.

Glycolysis is a fast, inefficient metabolic pathway used to produce energy from glucose in the absence of oxygen. Some cancer cells utilize glycolysis even when oxygen is present to facilitate their growth, which might be exploitable for cancer treatment.

Choi and co-workers confirmed that SA and a much more potent SA derivative from the licorice plant, amoB1, bound to ENO1 and PKM2, thereby blocking their activity in human cells. “These findings suggest SA can mediate anti-cancer and anti-inflammatory effects,” Choi said.

“In the BCBC, we use bioinformatics to make predictions,” said Powell. “So it’s pretty satisfying and exciting that the group was able to validate the top two candidate targets in the lab.”

To help predict other conditions that SA might treat, Choi searched a publicly available database containing gene–disease associations and found the genes encoding the 95 cSABPs were implicated in over 1,100 diseases across 22 physiological categories.

These results provide researchers with a roadmap to further investigate the cSABPs in disease and could also encourage drug and nutraceutical researchers to take a closer look at other plant-produced SA derivatives.

“So many medicinal plants are being used to treat pain, fever and inflammation; I bet that the active ingredient in many of them is a SA derivative,” Klessig said.

Klessig is also an adjunct professor of Plant Pathology and Plant-Microbe Biology at Cornell University. Strickler is director of BCBC and a senior research associate at BTI, and Powell is a postdoctoral scientist in her group. Co-author Frank Schroeder is a professor at BTI and in the Department of Chemistry and Chemical Biology at Cornell University.

The research was supported in part by a grant from the US National Science Foundation (IOS-0820405) and a grant from the National Research Foundation of Korea (2019R1F1A1060416).

Michael J. Haas is a freelance writer for Boyce Thompson Institute.