Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
Département de Pharmacochimie Moléculaire (DPM), UMR 5063, Univ. Grenoble Alpes, 38041 Grenoble, France.
Molecules. 2020 Feb 10;25(3):764. doi: 10.3390/molecules25030764.
The resistance of tumors against anticancer drugs is a major impediment for chemotherapy. Tumors often develop multidrug resistance as a result of the cellular efflux of chemotherapeutic agents by ABC transporters such as P-glycoprotein (ABCB1/P-gp), Multidrug Resistance Protein 1 (ABCC1/MRP1), or Breast Cancer Resistance Protein (ABCG2/BCRP). By screening a chemolibrary comprising 140 compounds, we identified a set of naturally occurring aurones inducing higher cytotoxicity against P-gp-overexpressing multidrug-resistant (MDR) cells versus sensitive (parental, non-P-gp-overexpressing) cells. Follow-up studies conducted with the P-gp inhibitor tariquidar indicated that the MDR-selective toxicity of azaaurones is not mediated by P-gp. Azaaurone analogs possessing pronounced effects were then designed and synthesized. The knowledge gained from structure-activity relationships will pave the way for the design of a new class of anticancer drugs selectively targeting multidrug-resistant cancer cells.
肿瘤对抗癌药物的耐药性是化疗的主要障碍。肿瘤通常会由于 ABC 转运蛋白（如 P 糖蛋白（ABCB1/P-gp）、多药耐药蛋白 1（ABCC1/MRP1）或乳腺癌耐药蛋白（ABCG2/BCRP））将化疗药物从细胞内排出而产生多药耐药性。通过筛选包含 140 种化合物的化学文库，我们发现了一组天然存在的奥罗内，它们对 P-糖蛋白过表达的多药耐药（MDR）细胞相对于敏感（亲本、非 P-糖蛋白过表达）细胞具有更高的细胞毒性。用 P-糖蛋白抑制剂他利喹达进行的后续研究表明，氮杂奥罗内的 MDR 选择性毒性不是由 P-糖蛋白介导的。然后设计并合成了具有明显效果的氮杂奥罗内类似物。从构效关系中获得的知识将为设计选择性针对多药耐药癌细胞的新型抗癌药物铺平道路。
