达那唑通过 STAT3/Myc 相关途径介导多药耐药癌细胞的交叉敏感性。

Danazol mediates collateral sensitivity via STAT3/Myc related pathway in multidrug-resistant cancer cells.

机构信息

Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC.

Department of Medicine, College of Medicine, I-Shou University, 8 Yida Road, Kaohsiung, 82445, Taiwan, ROC.

出版信息

Sci Rep. 2019 Aug 12;9(1):11628. doi: 10.1038/s41598-019-48169-2.

Multidrug resistance presents an obstacle in cancer treatment. Among numerous combative strategies, collateral sensitivity (CS) drugs have opened a new avenue to defeat cancer by exploiting selective toxicity against multidrug-resistant (MDR) cancer. In the present study, a clinically used synthetic steroid hormone, danazol, was investigated for its CS properties and cytotoxic mechanisms. Compared with natural hormones, danazol possessed a stronger selective cytotoxicity against MDR cancer cells. Danazol induced the arrest of MDR cancer cells at the G2/M phase and caspase-8-related early apoptosis. Furthermore, in MDR cancer cells, danazol reduced STAT3 phosphorylation as well as the expression of STAT3-regulated genes involved in cell survival, such as c-Myc, CDC25, and CDK1. Danazol also upregulated the cell cycle inhibitor p21 in MDR cancer cells. Supporting the experimental results, docking studies have revealed that danazol can likely bind favourably with STAT3. Taken together, our results suggest that danazol exerts a CS effect by inhibiting the STAT3 pathway in MDR cancer cells and thus provides a possible solution for MDR cancers.

多药耐药性是癌症治疗的一个障碍。在众多有针对性的策略中，协同敏感（CS）药物通过利用针对多药耐药（MDR）癌症的选择性毒性，为战胜癌症开辟了新途径。在本研究中，临床使用的合成甾体激素丹那唑被用于研究其 CS 特性和细胞毒性机制。与天然激素相比，丹那唑对 MDR 癌细胞具有更强的选择性细胞毒性。丹那唑诱导 MDR 癌细胞在 G2/M 期停滞，并引发 caspase-8 相关的早期细胞凋亡。此外，在 MDR 癌细胞中，丹那唑降低了 STAT3 磷酸化以及参与细胞存活的 STAT3 调节基因的表达，如 c-Myc、CDC25 和 CDK1。丹那唑还上调了 MDR 癌细胞中的细胞周期抑制剂 p21。基于实验结果，对接研究表明丹那唑可能与 STAT3 结合良好。综上所述，我们的研究结果表明，丹那唑通过抑制 MDR 癌细胞中的 STAT3 通路发挥 CS 作用，从而为治疗 MDR 癌症提供了一种可能的解决方案。