Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors

Abstract

Summary Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. While the role of NSAIDs as cyclooxygenase (COX) inhibitors is well established, other targets may contribute to anti-inflammation. Here we report caspases as a new pharmacological target for NSAID-family drugs such as ibuprofen, naproxen, and ketorolac at physiologic concentrations both in vitro and in vivo. We characterize caspase activity both in vitro and in cell culture, and combine computational modeling and biophysical analysis to determine the mechanism of action. We observe that inhibition of caspase catalysis reduces cell death and the generation of pro-inflammatory cytokines. Further, NSAID inhibition of caspases is COX-independent, representing a new anti-inflammatory mechanism. This finding expands upon existing NSAID anti-inflammatory behaviors, with implications for patient safety and next-generation drug design.

Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases

“…It is interesting to note that 3 out of the 4 FDA compounds capable of inhibiting caspase-3 activity, namely diflunisal, pranoprofen, and fenoprofen, are NSAIDs. We also observed other NSAIDs among the top 100 hits from our virtual screening, such as fenbufen (allosteric site rank: 11, orthosteric site rank: 76), and flufenamic acid (78, 272) which have been shown to have anti-caspase activity by Smith et al 29 but suggested that the NSAIDs could bind to the orthosteric S1 subsite. In…”

“…Since previous studies have ruled out the possibility of non-steroidal anti-inflammatory drugs (NSAIDs) inhibiting the activity of luciferase, we did not perform further studies on that prospect. 29 Initial screening was performed using 50 μM concentration of each compound and tested against caspase-3 enzyme activity. Diflunisal and pranoprofen showed maximal inhibition when compared with fenoprofen and flubendazole.…”

Non-apoptotic Caspase regulation of stem cell properties

“…In other cases such molecules are competitive inhibitors of caspase substrates, which prevent apoptotic-dependent tissue damage [104] . Caspase inhibitors have also been used to regulate the inflammatory response [105] and treat specific diseases [106] , [107] . However the inclusion of these molecules into the clinic has proven challenging [108] , [109] , [110] .…”

A Compendium of Kinetic Cell Death Modulatory Profiles Identifies Ferroptosis Regulators

“…Apart from the intended target, small molecules often have off-target effects on other proteins or processes. While these effects can confound the interpretation of large-scale studies, careful analysis can pinpoint unexpected mechanisms of action and new drug repurposing opportunities 12,[15][16][17][18] . Most largescale drug repurposing studies focus on protein off-targets, but compoundspecific chemical reactivities that can contribute to unanticipated biological effects within the cell, independent of protein engagement, are often ignored 19 .…”