Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †

Nagamani Vunnam, Malaney C. Young, Elly E. Liao, Chih Hung Lo, Evan Huber, Mary Jane Been, David D. Thomas, Jonathan N. Sachs

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Nimesulide is a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor with antitumor and antiproliferative activities that induces apoptosis in oral, esophagus, breast, and pancreatic cancer cells. Despite being removed from the market due to hepatotoxicity, nimesulide is still an important research tool being used to develop new anticancer drugs. Multiple studies have been done to modify the nimesulide skeleton to develop more potent anticancer agents and related compounds are promising scaffolds for future development. As such, establishing a mechanism of action for nimesulide remains an important part of realizing its potential. Here, we show that nimesulide enhances TRAIL-induced apoptosis in resistant pancreatic cancer cells by promoting clustering of DR5 in the plasma membrane. In this way, nimesulide acts like a related compound, DuP-697, which sensitizes TRAIL-resistant colon cancer cells in a similar manner. Our approach applies a time-resolved FRET-based biosensor that monitors DR5 clustering and conformational states in the plasma membrane. We show that this tool can be used for future high-throughput screens to identify novel, nontoxic small molecule scaffolds to overcome TRAIL resistance in cancer cells.

Original languageEnglish (US)
Article number2176692
JournalCancer Biology and Therapy
Volume24
Issue number1
DOIs
StatePublished - 2023

Bibliographical note

Funding Information:
This work was supported by U.S. National Institutes of Health (NIH) grants to J.N.S. (R35GM131814) and to D.D.T. (R01 HL139065). We thank Samantha Yuen from the David Thomas group for technical discussions.

Publisher Copyright:
© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.

Keywords

  • COX-2 inhibitors
  • Nimesulide
  • TNF-related apoptosis inducing ligand
  • death receptor 5
  • pancreatic cancer cells
  • tumor necrosis factor receptors

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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