Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.
Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA.
Chemistry. 2019 Jul 11;25(39):9206-9210. doi: 10.1002/chem.201902223. Epub 2019 Jun 26.
Complexes of the element Re have recently been shown to possess promising anticancer activity through mechanisms of action that are distinct from the conventional metal-based drug cisplatin. In this study, we report our investigations on the anticancer activity of the complex [Re(CO) (dmphen)(p-tol-ICN)] (TRIP) in which dmphen=2,9-dimethyl-1,10-phenanthroline and p-tol-ICN=para-tolyl isonitrile. TRIP was synthesized by literature methods and exhaustively characterized. This compound exhibited potent in vitro anticancer activity in a wide variety of cell lines. Flow cytometry and immunostaining experiments indicated that TRIP induces intrinsic apoptosis. Comprehensive biological mechanistic studies demonstrated that this compound triggers the accumulation of misfolded proteins, which causes endoplasmic reticulum (ER) stress, the unfolded protein response, and apoptotic cell death. Furthermore, TRIP induced hyperphosphorylation of eIF2α, translation inhibition, mitochondrial fission, and expression of proapoptotic ATF4 and CHOP. These results establish TRIP as a promising anticancer agent based on its potent cytotoxic activity and ability to induce ER stress.
近年来，研究表明，铼的配合物通过不同于传统金属药物顺铂的作用机制，具有有前景的抗癌活性。在这项研究中，我们报告了对配合物[Re(CO)(dmphen)(p-tol-ICN)]（TRIP）的抗癌活性的研究，其中 dmphen=2,9-二甲基-1,10-菲咯啉，p-tol-ICN=对甲苯异腈。TRIP 通过文献方法合成并进行了详细的表征。该化合物在多种细胞系中表现出很强的体外抗癌活性。流式细胞术和免疫染色实验表明，TRIP 诱导内在的细胞凋亡。全面的生物学机制研究表明，该化合物触发错误折叠蛋白的积累，导致内质网（ER）应激、未折叠蛋白反应和凋亡性细胞死亡。此外，TRIP 诱导 eIF2α 的过度磷酸化、翻译抑制、线粒体分裂以及促凋亡 ATF4 和 CHOP 的表达。这些结果表明，TRIP 是一种有前途的抗癌药物，其具有很强的细胞毒性活性和诱导 ER 应激的能力。
