Indomethacin elicits proteasomal dysfunctions develops apoptosis through mitochondrial abnormalities

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are a class of drugs that are mainly used to treat pain, inflammation, and fever via cyclooxygenase‐2 (COX‐2) inhibition. There are abundant findings that uncover the hidden critical chemotherapeutics potential of NSAIDs in cancer treatment. However, st...

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Bibliographic Details
Published in:	Journal of cellular physiology Vol. 233; no. 2; pp. 1685 - 1699
Main Authors:	Amanullah, Ayeman, Mishra, Ribhav, Upadhyay, Arun, Reddy, Pothula P., Das, Ranabir, Mishra, Amit
Format:	Journal Article
Language:	English
Published:	United States Wiley Subscription Services, Inc 01-02-2018
Subjects:	A549 Cells Abnormalities Accumulation Animals Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anticancer properties Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antitumor agents Apoptosis Apoptosis - drug effects Cancer Carcinogenesis Carcinogens Cercopithecus aethiops COS Cells Cyclooxygenase-2 Development strategies Dose-Response Relationship, Drug Fever Humans Indomethacin Indomethacin - chemistry Indomethacin - pharmacology Inflammation Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - pathology Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology mitochondrial abnormalities Molecular Docking Simulation Nonsteroidal anti-inflammatory drugs nonsteroidal anti‐inflammatory drugs (NSAIDs) Pain proteasome Proteasome Endopeptidase Complex - chemistry Proteasome Endopeptidase Complex - drug effects Proteasome Endopeptidase Complex - metabolism Proteasome inhibitors Proteasome Inhibitors - chemistry Proteasome Inhibitors - pharmacology Proteasomes Protein Aggregates Protein Binding Proteins Proteolysis Signal Transduction - drug effects Structure-Activity Relationship Substrates Time Factors Ubiquitin Ubiquitination proteasome apoptosis nonsteroidal anti-inflammatory drugs (NSAIDs) mitochondrial abnormalities indomethacin
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Summary:	Non‐steroidal anti‐inflammatory drugs (NSAIDs) are a class of drugs that are mainly used to treat pain, inflammation, and fever via cyclooxygenase‐2 (COX‐2) inhibition. There are abundant findings that uncover the hidden critical chemotherapeutics potential of NSAIDs in cancer treatment. However, still the precise mechanism by which NSAIDs could be used as an effective anti‐tumor agent in the prevention of carcinogenesis is not well understood. Here, we show that indomethacin, a well‐known NSAID, induces proteasomal dysfunction that results in accumulation of unwanted proteins, mitochondrial abnormalities, and successively stimulate apoptosis in cells. We observed the interaction of indomethacin with proteasome and noticed the massive accumulation of intracellular ubiquitin‐positive proteins, which might be due to the suppression of proteasome activities. Furthermore, we also found that exposure of indomethacin causes the accumulation of critical proteasomal substrates that consequently generate severe mitochondrial abnormalities and prompt up key apoptotic events in cells. Our results demonstrate how indomethacin affects normal proteasomal functions and induces mitochondrial apoptosis in cells. These findings also improve our current understanding of how NSAIDs can exhibit crucial anti‐proliferative effects in cells. In near future, our findings may suggest a new possible strategy for the development of specific proteasome inhibitors in conjunction with other chemo‐preventive anticancer agents. Indomethacin induces apoptosis through the disturbance of proteasome functions.
ISSN:	0021-9541 1097-4652
DOI:	10.1002/jcp.26081