Researchers at the University’s Boyce Thompson Institute have recently uncovered that aspirin might not be working the way most doctors think it does. Prof. Daniel Klessig, plant science at BTI, has been studying aspirin and its metabolite salicylic acid (S.A.) for the last 25 years. His most recent findings, published in Molecular Medicine earlier this year, offer an alternate explanation for how aspirin works, focusing on the interaction between S.A. and the body. These findings help account for some of aspirin’s unexplainable benefits, like how it reduces the risk of a variety of cancers.
Aspirin is one of the world’s most utilized drugs, with over 80 million tablets being consumed daily by Americans alone. Although normally taken to treat pain, swelling and fever, it also serves as a blood thinner.
Many doctors recommend daily low-dose of aspirin to prevent reoccurrence of heart attack, stroke or heart disease in elderly patients. Recent studies suggest that long-term use of aspirin may also reduce risk of colorectal cancer.
“The consensus of the biomedical community is that the primary, if not exclusive, mode of action of aspirin is inhibition of cyclooxygenases [COX] … enzymes that synthesize compounds called prostaglandins, which induce inflammation, swelling, pain and fever,” Klessig said.
When COX is inhibited by aspirin, it can no longer produce these compounds, according to Klessig. But research done at the BTI indicates that it is aspirin’s metabolite salicylic acid, that is causing the majority of the beneficial effects of aspirin. Previously, it was agreed that aspirin itself was directly acting on COX before it was metabolized, or broken down, in the body.
“There are two things that don’t fit this current consensus of how aspirin works. The first is that aspirin gets metabolized, or broken down, into salicylic acid in the body very quickly,” Klessig said. “Second, unlike aspirin, S.A. is a very weak inhibitor of COX activity, yet S.A. and aspirin have nearly the same beneficial pharmacological effects. Thus, we reasoned there must be additional targets through which aspirin/SA exerts its many effects.”
According to Klessig, researchers have previously discovered that S.A. is produced and used by plants to regulate their immune systems.
“We anticipated that S.A., like most other hormones in plants and animals, would act by binding to one or a few receptors. We struggled for the better part of 25 years trying to identify its receptor,” he said. “But rather than a single one, we uncovered dozens of different proteins through which S.A. modulates many plant processes, including immunity.”
Using high-through put screens developed to identify plant proteins to which S.A. binds, several proteins from human cells were identified.
The first is High Mobility Group Box 1 or HMGB1. Because of its role in promoting inflammation when outside the cell, HMGB1 is involved in many diseases such as heart disease, rheumatoid arthritis, lupus, sepsis, stroke and a variety of cancers.
“We found that S.A. at very low levels inhibits these pro-inflammatory activities of HMGB1,” Klessig said.
Since this low level is reached in the bloodstream of people taking a baby aspirin, the resulting inhibition of HMGB1’s pro-inflammatory activities may be responsible for the protective effect against certain cancers, such as colorectal cancer, of low-dose aspirin usage.
Another target is glyceraldehyde 3-phosphate-dehydrogenase or GAPDH. “GAPDH is a key suspect in a variety of neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s,” Klessig said. “In a model system, SA suppresses the neurodegenerative activity or the cell-death inducing activity that is associated with GAPDH. This work is still preliminary but has very exciting potential.”
Research on S.A. will also provide insight into some of the side effects of Aspirin, Klessig said. Negative side effects include potential stomach and intestinal ulcers, as well as an increased risk of bleeding from its blood-thinning effects.
“As we identify more and more of the targets of S.A., we will have a much better understanding, at the biochemical and molecular levels, of the basis of some of the negative side effects of aspirin,” he said.
In addition, BTI researchers have synthesized SA derivatives and located natural derivatives in licorice. These derivatives are 50-1000 times more potent than S.A. in aspirin, according to Klessig.
“We are convinced that with the knowledge we have acquired and the experimental tools we have, it will be possible to make a better aspirins, if you will,” Klessig said. “Certainly an aspirin that will do the job better, whatever that job may be, and perhaps with fewer negative side effects.”