title: Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.
abstract: 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 in 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.
authors.affiliation: Department of Chemistry & Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Smith
authors.affiliation: Department of Chemistry & Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Subada
authors.initials: S
authors.lastname: Soti
authors.affiliation: Department of Chemistry & Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Torey A
authors.initials: TA
authors.lastname: Jones
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Xue
authors.affiliation: Department of Chemistry & Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA. Electronic address: hubert.yin@colorado.edu.
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D061945:Caspase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D053471:Caspases, Initiator / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020910:Ketorolac / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009288:Naproxen / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D054852:Small Molecule Libraries; D009288:Naproxen; C093516:CASP4 protein, human; D020169:Caspases; D053471:Caspases, Initiator; D007052:Ibuprofen; D020910:Ketorolac
keywords: NSAIDs; anti-inflammation; caspase; pharmacology