Huang Xiao-Cong, Xiao Xue, Zhang Yun-Kai, Talele Tanaji T, Salim Angela A, Chen Zhe-Sheng, Capon Robert J
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Mar Drugs. 2014 Jun 27;12(7):3818-37. doi: 10.3390/md12073818.
ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 1-12 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure-activity relationship analysis inclusive of the natural products 1-12 and the synthetic analogues 13-19, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.
ATP结合盒（ABC）转运蛋白，如P-糖蛋白、乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白1（MRP1），可增加临床化疗药物的外排，并导致癌细胞产生多药耐药（MDR）。尽管迄今为止，临床上有用的抑制剂的发现和开发一直难以实现，但这个分子靶点仍然是解决并可能克服多药耐药的一个有前景的策略。在寻找新型抑制剂的过程中，我们利用细胞流式细胞术支持的荧光积累和外排测定以及多药耐药逆转测定，针对一组敏感和多药耐药的人类癌细胞系，评估海洋海绵共代谢物1 - 12作为P-糖蛋白、BCRP或MRP1引发的多药耐药的抑制剂。这些研究鉴定并表征了片螺素O（11）作为BCRP介导的药物外排的选择性抑制剂。在计算机对接研究的支持下，对天然产物1 - 12和合成类似物13 - 19进行的构效关系分析揭示了片螺素O（11）的BCRP抑制药效团的关键结构要求。
