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 1μM. Additionally, 1μM 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 0.14μM, and low concentrations of CBT-1® (