Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)-mediated transport by the orally administered inhibitor, CBT-1®

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 (R) 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 (R) completely inhibited rhodamine 123 transport from Pgp-overexpressing cells at a concentration of 1 mu M. Additionally, 1 mu M completely reversed Pgp-mediated resistance to vinblastine, paclitaxel and depsipeptide in SW620 Ad20 cells. CBT-1 (R), was found to compete [I-125]-IAPP labeling of Pgp with an IC50 of 0.14 mu M, and low concentrations of CBT-1 (R) (<1 mu M) stimulated Pgp-mediated ATP hydrolysis. in MRP1-overexpressing cells, 10 mu M CBT-1 (R) was found to completely inhibit MRPI-mediated calcein transport. CBT-1 (R) at 25 mu M did not have a significant effect on ABCG2-mediated pheophorbide a transport. Serum levels of CBT-1 (R) in samples obtained from eight patients receiving CBT-1 (R) increased intracellular rhodamine 123 levels in CD56+ cells 2.1- to 5.7-fold in an ex vivo assay. CBT-1 (R) is able to inhibit the ABC transporters Pgp and MRPI, making it an attractive candidate for clinical trials in cancers where Pgp and/or MRP1 might be overexpressed. Further clinical studies with CBT-1 (R) are warranted. (c) 2007 Elsevier Inc. All rights reserved.