title: Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)-mediated transport by the orally administered inhibitor, CBT-1((R)).
abstract: Cellular expression of ATP-binding cassette (ABC) transport proteins, such as P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), or ABCG2, is known to confer a drug-resistant phenotype. Thus, the development of effective transporter inhibitors could be of value to cancer treatment. CBT-1 is a bisbenzylisoquinoline plant alkyloid currently in development as a Pgp inhibitor. We characterized its interactions with the three major ABC transporters associated with drug resistance - Pgp, MRP1 and ABCG2 - and compared it to other known inhibitors. CBT-1 completely inhibited rhodamine 123 transport from Pgp-overexpressing cells at a concentration of 1muM. Additionally, 1 microM completely reversed Pgp-mediated resistance to vinblastine, paclitaxel and depsipeptide in SW620 Ad20 cells. CBT-1 was found to compete [(125)I]-IAAP labeling of Pgp with an IC(50) of 0.14 microM, and low concentrations of CBT-1 (<1 microM) stimulated Pgp-mediated ATP hydrolysis. In MRP1-overexpressing cells, 10 microM CBT-1 was found to completely inhibit MRP1-mediated calcein transport. CBT-1 at 25 microM did not have a significant effect on ABCG2-mediated pheophorbide a transport. Serum levels of CBT-1 in samples obtained from eight patients receiving CBT-1 increased intracellular rhodamine 123 levels in CD56+ cells 2.1- to 5.7-fold in an ex vivo assay. CBT-1 is able to inhibit the ABC transporters Pgp and MRP1, making it an attractive candidate for clinical trials in cancers where Pgp and/or MRP1 might be overexpressed. Further clinical studies with CBT-1 are warranted.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Finley
authors.forename: Robert K
authors.initials: RK
authors.lastname: Oldham
authors.forename: Daryl
authors.initials: D
authors.lastname: Barnett
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001386:Azides / Q000378:metabolism; D001685:Biological Factors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003524:Cyclosporins / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007313:Insecta; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases; D000470:Alkaloids; D000970:Antineoplastic Agents; D001386:Azides; D001685:Biological Factors; D003524:Cyclosporins; D047630:Depsipeptides; D005456:Fluorescent Dyes; D005472:Fluorouracil; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D011224:Prazosin; D011804:Quinolines; D020112:Rhodamine 123; D014700:Verapamil; D014747:Vinblastine; C513055:ABCB1 protein, human; C412039:CBT-1 (plant alkaloid); C041552:azidoprazosin; C402343:tariquidar; C070272:valspodar; C421109:multidrug resistance-associated protein 1