Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †
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 rese...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
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| Series: | Cancer Biology & Therapy |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15384047.2023.2176692 |
| _version_ | 1827595138696740864 |
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| author | Nagamani Vunnam Malaney C. Young Elly E. Liao Chih Hung Lo Evan Huber MaryJane Been David D. Thomas Jonathan N. Sachs |
| author_facet | Nagamani Vunnam Malaney C. Young Elly E. Liao Chih Hung Lo Evan Huber MaryJane Been David D. Thomas Jonathan N. Sachs |
| author_sort | Nagamani Vunnam |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T02:47:30Z |
| format | Article |
| id | doaj.art-8339f8f393c04b4cb0e30efbbd4b2ad7 |
| institution | Directory Open Access Journal |
| issn | 1538-4047 1555-8576 |
| language | English |
| last_indexed | 2024-03-09T02:47:30Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj.art-8339f8f393c04b4cb0e30efbbd4b2ad72023-12-05T15:58:14ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762023-12-0124110.1080/15384047.2023.21766922176692Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †Nagamani Vunnam0Malaney C. Young1Elly E. Liao2Chih Hung Lo3Evan Huber4MaryJane Been5David D. Thomas6Jonathan N. Sachs7University of MinnesotaUniversity of MinnesotaUniversity of MinnesotaUniversity of MinnesotaUniversity of MinnesotaUniversity of MinnesotaUniversity of MinnesotaUniversity of MinnesotaNimesulide 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.http://dx.doi.org/10.1080/15384047.2023.2176692nimesulidecox-2 inhibitorspancreatic cancer cellstumor necrosis factor receptorsdeath receptor 5tnf-related apoptosis inducing ligand |
| spellingShingle | Nagamani Vunnam Malaney C. Young Elly E. Liao Chih Hung Lo Evan Huber MaryJane Been David D. Thomas Jonathan N. Sachs Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering † Cancer Biology & Therapy nimesulide cox-2 inhibitors pancreatic cancer cells tumor necrosis factor receptors death receptor 5 tnf-related apoptosis inducing ligand |
| title | Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering † |
| title_full | Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering † |
| title_fullStr | Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering † |
| title_full_unstemmed | Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering † |
| title_short | Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering † |
| title_sort | nimesulide a cox 2 inhibitor sensitizes pancreatic cancer cells to trail induced apoptosis by promoting dr5 clustering † |
| topic | nimesulide cox-2 inhibitors pancreatic cancer cells tumor necrosis factor receptors death receptor 5 tnf-related apoptosis inducing ligand |
| url | http://dx.doi.org/10.1080/15384047.2023.2176692 |
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