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® 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 1 μM. Additionally, 1 μM completely reversed Pgp-mediated resistance to vinblastine, paclitaxel and depsipeptide in SW620 Ad20 cells. CBT-1® was found to compete [125I]-IAAP labeling of Pgp with an IC50 of 0.14 μM, and low concentrations of CBT-1® (<1 μM) stimulated Pgp-mediated ATP hydrolysis. In MRP1-overexpressing cells, 10 μM CBT-1® was found to completely inhibit MRP1-mediated calcein transport. CBT-1® at 25 μM 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.