title: Lamellarin O, a pyrrole alkaloid from an Australian marine sponge, Ianthella sp., reverses BCRP mediated drug resistance in cancer cells.
abstract: 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.
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia. xiaocong.huang@uqconnect.edu.au.
authors: Xiao-Cong
authors: XC
authors: Huang
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia. xue.xiao@imb.uq.edu.au.
authors: Xue
authors: X
authors: Xiao
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. helloyunyun@live.com.
authors: Yun-Kai
authors: YK
authors: Zhang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. talelet@stjohns.edu.
authors: Tanaji T
authors: TT
authors: Talele
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia. a.salim@imb.uq.edu.au.
authors: Angela A
authors: AA
authors: Salim
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. chenz@stjohns.edu.
authors: Zhe-Sheng
authors: ZS
authors: Chen
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia. r.capon@uq.edu.au.
authors: Robert J
authors: RJ
authors: Capon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D001315:Australia; D003374:Coumarins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005452:Fluoresceins / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008942:Mitoxantrone / Q000378:metabolism; D062105:Molecular Docking Simulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011161:Porifera / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003374:Coumarins; D004317:Doxorubicin; D005452:Fluoresceins; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human; C116876:lamellarin O; C007740:fluorexon; C421109:multidrug resistance-associated protein 1