Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †.
Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †.
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DOI：
10.1080/15384047.2023.2176692
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发表时间：
2023-12-31
影响因子：
3.6
通讯作者：
Sachs, Jonathan N.
中科院分区：
文献类型：
--
作者：
Vunnam, Nagamani;Young, Malaney C.;Liao, Elly E.;Lo, Chih Hung;Huber, Evan;Been, MaryJane;Thomas, David D.;Sachs, Jonathan N.
关键词：
尼美舒利是一种非类固醇抗炎药，也是一种环氧合酶-2抑制剂，具有抗肿瘤和抗增殖活性，可诱导口腔、食道、乳腺和胰腺癌细胞的凋亡。尽管尼美舒利因肝毒性而退出市场，但它仍然是用于开发抗癌新药的重要研究工具。人们已经进行了大量的研究来修饰尼美舒利骨架以开发更有效的抗癌药物，相关化合物是未来发展的有前途的支架材料。因此，建立尼美舒利的作用机制仍然是实现其潜力的重要部分。在这里，我们展示了尼美舒利通过促进DR5在细胞膜上的聚集来增强TRAIL诱导的耐药胰腺癌细胞的凋亡。在这种情况下，尼美舒利的作用类似于相关化合物DUP-697，它以类似的方式使耐TRAIL的结肠癌细胞敏化。我们的方法应用了一种基于时间分辨FRET的生物传感器，它可以监测质膜中DR5的聚集和构象状态。我们表明，该工具可以用于未来的高通量筛选，以确定新的、无毒的小分子支架，以克服癌细胞中的TRAIL耐药性。
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.
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DOI：
10.3390/molecules15031873
发表时间：
2010-03-15
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Jia S;Hu C
通讯作者：
Hu C
影响因子：
4.7
作者：
Ferreira RG;Narvaez LEM;Espíndola KMM;Rosario ACRS;Lima WGN;Monteiro MC
通讯作者：
Monteiro MC
影响因子：
8
作者：
Dimberg LY;Anderson CK;Camidge R;Behbakht K;Thorburn A;Ford HL
通讯作者：
Ford HL
影响因子：
2.9
作者：
Eibl, G;Reber, HA;Hines, OJ
通讯作者：
Hines, OJ
影响因子：
4.8
作者：
Hu, G;Jang, GF;Palczewski, K
通讯作者：
Palczewski, K