title: Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C.
abstract: Inhibitors of the breast cancer resistance protein (BCRP/ABCG2) multidrug transporter are of interest as chemosensitizers for clinical drug resistance, for improving the pharmacokinetics of substrate chemotherapeutic drugs, and in functional assays of BCRP activity for tailoring chemotherapy. The fungal toxin fumitremorgin C (FTC) is a potent and specific inhibitor of BCRP, but its neurotoxic effects preclude use in vivo. We have therefore evaluated a new tetracyclic analogue of FTC, Ko143, as a practical inhibitor of BCRP, comparing it with two other analogues in the same class and with GF120918. All three FTC analogues are effective inhibitors of both mouse Bcrp1 and human BCRP, proving highly active for increasing the intracellular drug accumulation and reversing Bcrp1/BCRP-mediated multidrug resistance. Indeed, Ko143 appears to be the most potent BCRP inhibitor known thus far. In contrast, the compounds have only low activity against P-glycoprotein, the multidrug resistance-associated protein (MRP1), or other known drug transporters. They are nontoxic in vitro at useful concentrations and evinced no signs of toxicity in mice at high oral or i.p. doses. Administered p.o. to inhibit intestinal Bcrp1, Ko143 markedly increased the oral availability of topotecan in mice. It is thus the first highly potent and specific BCRP inhibitor applicable in vivo. As such, Ko143 and other FTC analogues of this type represent valuable reagents for analysis of drug resistance mechanisms and may be candidates for development as clinical BCRP inhibitors.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
authors.forename: John D
authors.initials: JD
authors.lastname: Allen
authors.forename: Arnold
authors.initials: A
authors.lastname: van Loevezijn
authors.forename: Jeany M
authors.initials: JM
authors.lastname: Lakhai
authors.forename: Martin
authors.initials: M
authors.lastname: van der Valk
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Glen
authors.initials: G
authors.lastname: Reid
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Koomen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects*; D051379:Mice; D008942:Mitoxantrone / Q000494:pharmacology; D009183:Mycotoxins / Q000031:analogs & derivatives / Q000494:pharmacology*; D009363:Neoplasm Proteins; D019772:Topotecan / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; 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; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D009183:Mycotoxins; D009363:Neoplasm Proteins; D014750:Vincristine; D019772:Topotecan; D008942:Mitoxantrone; C010522:tryptoquivaline