Bai Jie, Wang Rui-Hui, Qiao Yan, Wang Aidong, Fang Chen-Jie
Department of Chemical Biology, School of Pharmaceutical Sciences, Capital Medical University, Beijing.
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan.
Drug Des Devel Ther. 2017 Jul 31;11:2227-2237. doi: 10.2147/DDDT.S138371. eCollection 2017.
Multidrug resistance (MDR) is a huge obstacle in cancer chemotherapeutics. Overcoming MDR is a great challenge for anticancer drug discovery. Here, DNA binding and cytotoxicity of Schiff base L1 and L2 were explored to assess their efficiency in fighting cancer and overcoming the MDR. L1 and L2 could treat extremely chemoresistant MCF-7/ADR cell as drug-sensitive cell, with drug resistance index (DRI) <2.13, showing high potential in overcoming the MDR. The apoptotic ratio induced by L1 and L2 was low for both MCF-7 and MCF-7/ADR cells. L1 and L2 induced an impairment of cell cycle progression of MCF-7 and MCF-7/ADR cell lines and suppressed cell growth by perturbing progress through the G0/G1 phase, with L2 causing more profound effect, which might account for lower drug resistance after L2 treatment. The molecular docking revealed weak interaction between L1/L2 and P-glycoprotein (P-gp), the most important drug efflux pump and intracellular Rhodamine 123 accumulation indicated that the activity of P-gp was not inhibited by L1 and L2. Combined with the cellular uptake results, it implied that L1 and L2 could bypass P-gp efflux to exert anticancer activity.
多药耐药性（MDR）是癌症化疗中的一个巨大障碍。克服MDR是抗癌药物研发面临的巨大挑战。在此，对席夫碱L1和L2的DNA结合及细胞毒性进行了研究，以评估它们在抗癌和克服MDR方面的效果。L1和L2可将具有极强化疗耐药性的MCF-7/ADR细胞当作药敏细胞来处理，耐药指数（DRI）<2.13，显示出在克服MDR方面具有很高的潜力。L1和L2对MCF-7和MCF-7/ADR细胞诱导的凋亡率都很低。L1和L2诱导MCF-7和MCF-7/ADR细胞系的细胞周期进程受损，并通过干扰G0/G1期进程来抑制细胞生长，其中L2的作用更为显著，这可能是L2处理后耐药性较低的原因。分子对接显示L1/L2与P-糖蛋白（P-gp）之间的相互作用较弱，P-gp是最重要的药物外排泵，细胞内罗丹明123的积累表明L1和L2并未抑制P-gp的活性。结合细胞摄取结果，这意味着L1和L2可以绕过P-gp外排来发挥抗癌活性。
