Zhao Jianfu, Zeng Delong, Liu Yuedan, Luo Yi, Ji Shengbin, Li Xiaoling, Chen Tianfeng
Department of Chemistry, Jinan University, Guangzhou 510632, China.
Metallomics. 2017 May 24;9(5):535-545. doi: 10.1039/c7mt00001d.
Hyperglycemia is an important factor for chemoresistance of breast cancer patients with diabetes. In the present study, a novel selenadiazole derivative has been evaluated and found to be able to antagonize the doxorubicin (DOX) resistance of MCF-7 cells under simulated diabetes conditions. Hyperglycemia promotes the proliferation, invasion and migration of MCF-7 cells through activation of ERK and AKT pathways, which could be inhibited by the synthetic selenadiazole derivative. The antitumor effects of the selenadiazole derivative were attributed to its ability to activate AMPK pathways. Furthermore, the high lipophilicity (log P = 1.9) of the synthetic selenadiazole derivative facilitated its uptake by cancer cells and subsequently potentiated the cellular uptake of DOX, leading to a strong enhancment of the antiproliferative activity of DOX on MCF-7 cells by induction of apoptosis. The apoptosis was initiated by the ROS overproduction induced by the cooperation of the selenadiazole derivative and DOX. The excessive ROS then caused damage to DNA, which upregulated the expression of proapoptosis Bcl-2 family proteins and led to fragmentation of mitochondria, which finally caused apoptosis of the cancer cells. Taken together, this study provides a rational strategy for using selenadiazole derivatives to overcome hyperglycemia-induced drug resistance in breast cancer by activation of AMPK-mediated pathways.
高血糖是糖尿病乳腺癌患者化疗耐药的一个重要因素。在本研究中，一种新型硒二唑衍生物已被评估，发现在模拟糖尿病条件下能够拮抗MCF-7细胞对阿霉素（DOX）的耐药性。高血糖通过激活ERK和AKT途径促进MCF-7细胞的增殖、侵袭和迁移，而合成的硒二唑衍生物可以抑制这些途径。硒二唑衍生物的抗肿瘤作用归因于其激活AMPK途径的能力。此外，合成的硒二唑衍生物的高亲脂性（log P = 1.9）促进了癌细胞对其摄取，随后增强了DOX的细胞摄取，通过诱导凋亡导致DOX对MCF-7细胞的抗增殖活性显著增强。凋亡是由硒二唑衍生物和DOX协同诱导的ROS过量产生引发的。过量的ROS随后导致DNA损伤，上调促凋亡Bcl-2家族蛋白的表达并导致线粒体碎片化，最终导致癌细胞凋亡。综上所述，本研究为通过激活AMPK介导的途径使用硒二唑衍生物克服乳腺癌中高血糖诱导的耐药性提供了合理策略。
