Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.
Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA.
Angew Chem Int Ed Engl. 2020 Aug 3;59(32):13391-13400. doi: 10.1002/anie.202004883. Epub 2020 May 27.
Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO) (dmphen)(ptolICN)] , where dmphen=2,9-dimethyl-1,10-phenanthroline and ptolICN=para-tolyl isonitrile, called TRIP. This TRIP-resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild-type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP-resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184-fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP-binding cassette transporter P-glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.
铼三羰基配合物最近被研究为新型抗癌药物。然而，人们对它们的作用机制以及癌细胞对这些化合物慢性暴露的反应方式知之甚少。为了更深入地了解这些铼类抗癌药物，我们开发并鉴定了一种对先前研究的化合物[Re(CO) (dmphen)(ptolICN)]具有抗性的卵巢癌细胞系，其中 dmphen=2,9-二甲基-1,10-菲咯啉，ptolICN=对甲苯异腈，称为 TRIP。与野生型 A2780 卵巢癌细胞系相比，这种 TRIP 抗性卵巢癌细胞系 A2780TR 对 TRIP 的敏感性降低了 9 倍。此外，还测定了在 TRIP 抗性细胞系中已建立的药物和其他铼类抗癌药物的细胞毒性。值得注意的是，在 A2780TR 细胞系中，药物紫杉醇的活性降低了 184 倍，这表明 TRIP 和这种药物的耐药机制相似。因此，发现 ATP 结合盒转运蛋白 P-糖蛋白的表达水平升高，P-糖蛋白是一种已知能使紫杉醇解毒的外排转运蛋白。此外，使用国家癌症研究所 60 细胞系面板进行的基因表达分析表明，MT1E 基因在对 TRIP 敏感性较低的细胞中过度表达。由于该基因编码金属硫蛋白，因此该结果表明，该蛋白类的解毒是对 TRIP 产生耐药性的另一种机制。还评估了该基因在 A2780TR 细胞系中的重要性，证实该基因在该细胞系中的表达也升高了。作为第一项研究，该报告调查并确定了对铼配合物的癌细胞耐药途径，突出了卵巢癌细胞对 TRIP 和传统药物的耐药反应的重要相似性和差异性。
