Insights into interactions between taxanes and P-glycoprotein using biophysical and in silico methods

Multidrug resistance mediated by P-glycoprotein (Pgp) is a significant obstacle to cancer chemotherapy. Taxane drugs, including paclitaxel, docetaxel, and cabazitaxel, are used to treat multiple types of cancer. All taxane drugs are Pgp substrates, but cabazitaxel is also a Pgp inhibitor, indicating potential differential interactions between Pgp and different taxanes. Here, we showed for the first time that cabazitaxel had a partial inhibitory effect on the ATPase activity at concentrations higher than 10 µM. We found the K_D of paclitaxel, docetaxel, and cabazitaxel to Pgp are 0.85 µM, 40.59 µM, and 13.53 µM, respectively. Based on acrylamide quenching, paclitaxel induced Pgp into a wide inward-facing open conformation at a high concentration but a slightly occluded conformation at lower concentrations. Both docetaxel and cabazitaxel shifted Pgp towards occluded states, each drug resulting in a unique degree of occlusion. Furthermore, molecular docking and energy calculations revealed that cabazitaxel binds with the "access tunnel" and blocks the subsequent nucleotide-binding domain dimerization. Our results indicate that the preference of taxanes for different binding sites on Pgp leads to distinct transport mechanisms. These results provide valuable insight into the interaction between taxanes and Pgp, which will enhance future drug development.