Multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy, and the main cause of MDR has been attributed to overexpression of P-glycoprotein (P-gp). In this present study, four P-gp modulators (E,E)-4,6-bis(styryl)-2-(substituted amino)-pyrimidines were evaluated for their activity in a breast cancer cell line overexpressing P-gp (LCC6MDR). The four modulators displayed significantly better P-gp modulating activity compared with the positive control verapamil (RF = 5.4), with a relative fold (RF) increase in activity ranging from 33.3 to 86.0. In contrast to compounds a and c that exhibited lower cytotoxicity, compounds b and d were nontoxic towards both cancer cells and normal cells, with IC50 values greater than 100 μmol/L. The qRT-PCR results demonstrated that after exposure to 2 μmol/L of compounds a, b, c, and d, the mRNA expression level of MDR1 in LCC6MDR cells decreased to 45%, 50%, 38%, and 51%, respectively. However, the Western-blot results indicated that compound c could reverse P-gp mediated MDR, but not via decreases in protein expression. DOX and Rh123 accumulation and efflux results further confirmed that the reversal of MDR activity happens via inhibition of P-gp efflux and increases in intracellular drug accumulation. These results demonstrated that compound c has low toxicity and is an efficient P-gp modulator, highlighting its potential as a promising candidate for P-gp-mediated reversal of MDR.

中文翻译：

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新型姜黄素类似物在耐紫杉醇的人乳腺癌细胞中逆转P-糖蛋白介导的多药耐药性。

多药耐药性（MDR）是成功进行癌症化疗的主要障碍，并且MDR的主要原因是P-糖蛋白（P-gp）的过度表达。在本研究中，评估了四种P-gp调节剂（E，E）-4,6-双（苯乙烯基）-2-（取代的氨基）-嘧啶在过表达P-gp（LCC6MDR）的乳腺癌细胞系中的活性）。与阳性对照维拉帕米（RF = 5.4）相比，四种调节剂显示出明显更好的P-gp调节活性，活性的相对倍数（RF）增加，范围为33.3至86.0。与表现出较低细胞毒性的化合物a和c相比，化合物b和d对癌细胞和正常细胞均无毒，IC50值大于100μmol/ L。qRT-PCR结果表明，暴露于2μmol/ L的化合物a，b，c和d后，LCC6MDR细胞中MDR1的mRNA表达水平分别降至45％，50％，38％和51％。但是，Western-blot结果表明化合物c可以逆转P-gp介导的MDR，但不能通过蛋白质表达的降低来逆转。DOX和Rh123积聚和外排结果进一步证实，MDR活性的逆转是通过抑制P-gp外排和增加细胞内药物积聚而发生的。这些结果证明化合物c具有低毒性，并且是有效的P-gp调节剂，突出了其作为P-gp介导的MDR逆转的有希望的候选者的潜力。DOX和Rh123积聚和外排结果进一步证实，MDR活性的逆转是通过抑制P-gp外排和增加细胞内药物积聚而发生的。这些结果证明化合物c具有低毒性，并且是有效的P-gp调节剂，突出了其作为P-gp介导的MDR逆转的有希望的候选者的潜力。DOX和Rh123积聚和外排结果进一步证实，MDR活性的逆转是通过抑制P-gp外排和增加细胞内药物积聚而发生的。这些结果证明化合物c具有低毒性，并且是有效的P-gp调节剂，突出了其作为P-gp介导的MDR逆转的有希望的候选者的潜力。