Liu Yuedan, Luo Yi, Li Xiaoling, Zheng Wenjie, Chen Tianfeng
Department of Chemistry, Jinan University, Guangzhou 510631 (P. R. China).
Chem Asian J. 2015 Mar;10(3):642-52. doi: 10.1002/asia.201403409. Epub 2015 Jan 29.
Hyperglycemia is an important factor for chemoresistance of hepatocellular carcinoma patients with diabetes to therapeutics. In the present study, a series of selenadiazole derivatives have been rationally designed, synthesized, and found be able to antagonize drug resistance in HepG2 cells to doxorubicin (DOX) under simulated diabetes conditions. Hyperglycemia could promote the cell proliferation through upregulation of ERK and AKT phosphorylation. However, the synthetic selenadiazole derivatives effectively potentiated the cellular uptake of DOX and enhanced the antiproliferative activity of DOX on HepG2 cells by induction of apoptosis, via regulation of ROS-mediated AMPK activation, inhibition of mTORC1, and an increase in DNA damage. The selenadiazole derivatives that possess an increased lipophilicity could enhance the cellular uptake and anticancer efficacy of DOX. Taken together, this study provides a rational design strategy of selenadiazole derivatives to overcome hyperglycemia-induced drug resistance.
高血糖是糖尿病肝癌患者化疗耐药的重要因素。在本研究中，一系列硒二唑衍生物经过合理设计、合成，并发现其在模拟糖尿病条件下能够拮抗HepG2细胞对阿霉素（DOX）的耐药性。高血糖可通过上调ERK和AKT磷酸化来促进细胞增殖。然而，合成的硒二唑衍生物通过调节ROS介导的AMPK激活、抑制mTORC1以及增加DNA损伤，有效增强了DOX的细胞摄取，并通过诱导凋亡增强了DOX对HepG2细胞的抗增殖活性。具有增加亲脂性的硒二唑衍生物可增强DOX的细胞摄取和抗癌疗效。综上所述，本研究提供了一种合理设计硒二唑衍生物以克服高血糖诱导的耐药性的策略。
