Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland.
Department of Organic Chemistry, Medical University of Silesia, Jagiellonska 4, 41-200 Sosnowiec, Poland.
Int J Mol Sci. 2024 Sep 8;25(17):9732. doi: 10.3390/ijms25179732.
Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this phenomenon. There are few reports in the literature that selenium compounds can modulate the activity of P-glycoprotein (MDR1). Therefore, we performed in silico studies and evaluated the effects of the novel selenoesters EDAG-1 and EDAG-8 on BCRP, MDR1, and MRP1 resistance proteins in MCF-7 and MDA-MB-231 breast cancer cells. The cytometric analysis showed that the tested compounds (especially EDAG-8) are inhibitors of BCRP, MDR1, and MRP1 efflux pumps (more potent than the reference compounds-novobiocin, verapamil, and MK-571). An in silico study correlates with these results, suggesting that the compound with the lowest binding energy to these transporters (EDAG-8) has a more favorable spatial structure affecting its anticancer activity, making it a promising candidate in the development of a novel anticancer agent for future breast cancer therapy.
乳腺癌是全球所有恶性肿瘤中发病率最高的。其高死亡率主要与多药耐药的发生有关，这显著限制了治疗选择。在这方面，迫切需要开发能够克服这种现象的化合物。文献中很少有报道表明硒化合物可以调节 P-糖蛋白（MDR1）的活性。因此，我们进行了计算机模拟研究，并评估了新型硒酯 EDAG-1 和 EDAG-8 对 MCF-7 和 MDA-MB-231 乳腺癌细胞中 BCRP、MDR1 和 MRP1 耐药蛋白的影响。细胞计量分析表明，测试的化合物（尤其是 EDAG-8）是 BCRP、MDR1 和 MRP1 外排泵的抑制剂（比参考化合物-新生霉素、维拉帕米和 MK-571 更有效）。计算机模拟研究与这些结果相关，表明与这些转运蛋白结合能最低的化合物（EDAG-8）具有更有利的空间结构，影响其抗癌活性，使其成为未来乳腺癌治疗中开发新型抗癌药物的有前途的候选物。
