Researchers uncovered a previously unknown pathway of activity for NSAIDs (non-steroidal anti-inflammatory drugs).
The findings could be used to expand uses for NSAIDs or design next-generation therapies.
The mechanisms by which NSAIDs relieve inflammation are more complex than once thought.Nikesidoroff/iStock/Thinkstock
Scientists sometimes find novel uses for old drugs. For example, the common pain reliever aspirin is now used by millions of people to help prevent heart attack, stroke, or certain cancers. Aspirin is a type of non-steroidal anti-inflammatory drug (NSAID). Because aspirin has found multiple uses, other NSAIDs might also have health benefits that haven’t yet been discovered.
Inflammation is the body’s normal reaction to injury or disease. The result is redness, swelling, pain, and warmth in the inflamed area of the body. Although the inflammatory response enables the body to heal after injury, long-term inflammation has been linked to the development of cancer and other diseases. The sudden widespread and exaggerated inflammation in sepsis can result in tissue damage, organ failure, and even death.
Previous research has revealed some of the molecular mechanisms involved in inflammation. Aspirin and other NSAIDs are known to have anti-inflammatory effects by inhibiting COX (cyclooxygenase) enzymes. These enzymes are pivotal in the inflammatory process.
A research team led by Dr. Hang Hubert Yin of the University of Colorado, Boulder, and the BioFrontiers Institute used high-throughput screening to test nearly 1,300 FDA-approved drugs for anti-inflammatory activity. The team focused on another group of enzymes called caspases that are known to be important for inflammation and thus might also serve as useful therapeutic targets. The work was funded by NIH’s National Institute of General Medical Sciences (NIGMS). Results appeared in Cell Chemical Biology on February 23, 2017.
The team first ranked the drugs by their ability to inhibit the activity of the caspase-4 enzyme. They found 27 compounds that inhibited caspase-4 activity to less than 25%. Of these, about half—and 8 of the top 10 most potent—were NSAIDs. Further tests of 9 selected NSAIDs showed that all except aspirin inhibited multiple caspases.
In human cells, the caspases were inhibited by the same NSAIDs in the same rank order as in the high-throughput screen. Fenbufen and indoprofen were the strongest inhibitors; naproxen and ibuprofen were weak inhibitors; and aspirin was ineffective. In additional experiments, the team found that the NSAID inhibition of caspase was independent of COX enzymes.
“NSAIDs like ibuprofen and aspirin are among the most prevalent pharmaceuticals worldwide, with over 30 billion doses taken annually in the United States alone. But their precise mechanisms of action are not entirely understood,” Yin says. “We provide the first evidence for a novel mechanism of action for NSAIDs.”
Caspases are known to play a role in inflammatory diseases such as rheumatoid arthritis and heart disease. This newly discovered mechanism of NSAID activity suggests future studies into how these drugs affect caspases in the human body. The results could inform strategies to fight inflammation with fewer side effects.
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