Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
Eur J Med Chem. 2019 Oct 15;180:350-366. doi: 10.1016/j.ejmech.2019.05.053. Epub 2019 May 29.
Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound MY3 had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that MY3 could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, MY3 significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight. Therefore, MY3 might represent a promising lead to develop MDR reversal agents for cancer chemotherapy.
P-糖蛋白（P-gp）的过度表达是多药耐药（MDR）的主要原因之一，这已成为癌症治疗的主要障碍。逆转 MDR 的一种有希望的方法是开发表达和/或功能的 P-gp 抑制剂。在这里，我们设计并合成了一系列查尔酮衍生物作为 P-gp 抑制剂，并评估了它们对 MDR 的潜在逆转活性。其中，最活跃的化合物 MY3 具有很小的固有细胞毒性，并且在逆转 MCF-7/DOX 细胞中的 DOX 耐药性方面显示出最高的活性（RF=50.19）。进一步的研究表明，MY3 可以增加 DOX 的细胞内积累并抑制 P-gp 在 mRNA 和蛋白质水平上的表达。更重要的是，MY3 在不改变体重的情况下，显著增强了 DOX 对荷有 MCF-7/DOX 细胞的肿瘤异种移植物的疗效。因此，MY3 可能代表开发癌症化疗中 MDR 逆转剂的有前途的先导化合物。
