title: Reversal of ABCG2-mediated multidrug resistance by human cathelicidin and its analogs in cancer cells.
abstract: 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.
authors.affiliation: 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. kennethto@cuhk.edu.hk
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.forename: S X
authors.initials: SX
authors.lastname: Ren
authors.forename: C C M
authors.initials: CC
authors.lastname: Wong
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D054804:Cathelicidins
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010455:Peptides; D008942:Mitoxantrone; D054804:Cathelicidins