Reversal of P-glycoprotein and multidrug-resistance protein-mediated drug resistance in KB cells by 5-O-benzoylated taxinine K

A newly synthesized taxoid originally from the Japanese yew Taxus cuspidata , 5-O-benzoylated taxinine K (BTK) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein (MRP)-mediated multi drug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (AD M), and vincristine (VCR) of KB-8-5 and KB-C2 cells that overexpress P-gp b y directly interacting with P-gp. BTK also moderately reversed the resistan ce to ADM of KB/MRP cells that overexpress MRP. However, BTK neither inhibi ted the transporting activity of MRP nor reduced intracellular glutathione levels in KB/MRP cells. BTK shifted the distribution of ADM in KB/MRP cells from punctate cytoplasmic compartments to the nucleoplasm and cytoplasm by inhibiting acidification of cytoplasmic organelles. These two functions of BTK make it able to reverse both P-gp- and MRP-mediated MDR. BTK in combin ation with ADM should be useful for treating patients with tumors that over express both P-gp and MRP.