Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Cancer Biol Ther. 2023 Dec 31;24(1):2176692. doi: 10.1080/15384047.2023.2176692.
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.
尼美舒利是一种非甾体抗炎药和 COX-2 抑制剂，具有抗肿瘤和抗增殖活性，能诱导口腔癌、食管癌、乳腺癌和胰腺癌细胞凋亡。尽管因其肝毒性已从市场上撤出，但尼美舒利仍是一种重要的研究工具，用于开发新的抗癌药物。已经进行了多项研究来修饰尼美舒利骨架，以开发更有效的抗癌药物，相关化合物是未来开发的有前途的支架。因此，确定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，我们表明尼美舒利通过促进 DR5 在质膜中的聚集来增强 TRAIL 诱导的耐药胰腺癌细胞凋亡。这样，尼美舒利的作用类似于 DuP-697 等相关化合物，以类似的方式使 TRAIL 耐药结肠癌细胞敏感。我们的方法应用了一种基于时间分辨荧光共振能量转移的生物传感器，该传感器可监测质膜中 DR5 的聚集和构象状态。我们表明，该工具可用于未来的高通量筛选，以鉴定新的、无毒的小分子支架，以克服癌细胞对 TRAIL 的耐药性。
