title: Parguerenes: Marine red alga bromoditerpenes as inhibitors of P-glycoprotein (ABCB1) in multidrug resistant human cancer cells.
abstract: High intrinsic or acquired expression of membrane spanning, adenosine triphosphate binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp), in cancers represents a major impediment to chemotherapy, with accelerated drug efflux leading to multi-drug resistance (MDR). Although ABC transporter inhibitors offer the prospect of reversing the MDR phenotype, no inhibitors have advanced to the clinic. We employed a range of intracellular fluorescence and radio-ligand accumulation and efflux assays, together with cytotoxicity and MDR reversal assays, as well as flow cytometry, fluorescence microscopy and radioimmunoprecipitation, to discover and evaluate new P-gp inhibitors from a unique library of southern Australian and Antarctic marine natural products. This study successfully characterized two rare bromoditerpenes, parguerenes I and II, sourced from a southern Australian collection of the red alga Laurencia filiformis, as P-gp inhibitors. We determined that the parguerenes were non-cytotoxic, dose-dependent inhibitors of P-gp mediated drug efflux, that modify the extracellular antibody binding epitope of P-gp in a manner that differs markedly from that of the known inhibitors verapamil and cyclosporine A. We confirmed that parguerenes were capable of reversing P-gp mediated vinblastine, doxorubicin and paclitaxel MDR, that inhibitory properties span both P-gp and multidrug resistant protein 1 (MRP1), but do not extend to breast cancer resistance protein (BCRP), and that parguerene II is superior (more potent) to verapamil. Our investigations validate the proposition that marine natural products can deliver new ABC transporter inhibitor scaffolds, with structure characteristics fundamentally different from existing inhibitor classes.
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
authors: Xiao-Cong
authors: XC
authors: Huang
authors: Yue-Li
authors: YL
authors: Sun
authors: Angela A
authors: AA
authors: Salim
authors: Zhe-Sheng
authors: ZS
authors: Chen
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; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D044722:Laurencia / Q000737:chemistry*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D017239:Paclitaxel / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology
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; D000970:Antineoplastic Agents; D002945:Cisplatin; D004224:Diterpenes; D004317:Doxorubicin; D005452:Fluoresceins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D014747:Vinblastine; C581164:15-bromoparguer-9(11)-ene-2,7,16,19-tetrol-2,7,16,19-tetraacetate; C581163:15-bromoparguer-9(11)-ene-2,7,16,19-tetrol-2,7,16-triacetate; C116614:ABCG2 protein, human; C085925:calcein AM; C421109:multidrug resistance-associated protein 1