School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Room 801N, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Shatin, New Territories, Hong Kong, China.
Peptides. 2013 Feb;40:13-21. doi: 10.1016/j.peptides.2012.12.019. Epub 2012 Dec 27.
Multidrug resistance (MDR) of cancer cells to a wide spectrum of anticancer drugs is a major obstacle to successful chemotherapy. It is usually mediated by the overexpression of one of the three major ABC transporters actively pumping cytotoxic drugs out of the cells. There has been great interest in the search for inhibitors toward these transporters with an aim to circumvent resistance. This is usually achieved by screening from natural product library and the subsequent structural modifications. This study reported the reversal of ABCG2-mediated MDR in drug-selected resistant cancer cell lines by a class of host defense antimicrobial peptides, the human cathelicidin LL37 and its fragments. The effective human cathelicidin peptides (LL17-32 and LL13-37) were found to increase the accumulation of mitoxantrone in cancer cell lines with ABCG2 overexpression, thereby circumventing resistance to mitoxantrone. At the effective concentrations of the cathelicidin peptides, cell proliferation of the parental cells without elevated ABCG2 expression was not affected. Result from drug efflux and ATPase assays suggested that both LL17-32 and LL13-37 interact with ABCG2 and inhibit its transport activity in an uncompetitive manner. The peptides were also found to downregulate ABCG2 protein expression in the resistant cells, probably through a lysosomal degradation pathway. Our data suggest that the human cathelicidin may be further developed for sensitizing resistant cancer cells to chemotherapy.
癌细胞对多种抗癌药物的多药耐药性（MDR）是化疗成功的主要障碍。这通常是由三种主要 ABC 转运蛋白之一的过度表达介导的，这些蛋白主动将细胞毒性药物泵出细胞。人们对寻找这些转运蛋白的抑制剂产生了极大的兴趣，目的是规避耐药性。这通常通过从天然产物文库中筛选和随后的结构修饰来实现。本研究报道了一类宿主防御性抗菌肽，人源杀菌肽 LL37 及其片段逆转 ABCG2 介导的耐药性。发现有效的人源杀菌肽（LL17-32 和 LL13-37）可增加 ABCG2 过表达的癌细胞系中米托蒽醌的积累，从而规避米托蒽醌的耐药性。在杀菌肽的有效浓度下，未升高 ABCG2 表达的亲本细胞的细胞增殖不受影响。药物外排和 ATP 酶测定的结果表明，LL17-32 和 LL13-37 均与 ABCG2 相互作用，并以非竞争性方式抑制其转运活性。这些肽还被发现可下调耐药细胞中的 ABCG2 蛋白表达，可能通过溶酶体降解途径。我们的数据表明，人源杀菌肽可进一步开发用于使耐药癌细胞对化疗敏感。
