Vol. 58, Issue 6, 1563-1569, December 2000

Reversal of P-Glycoprotein and Multidrug-Resistance Protein-Mediated Drug Resistance in KB Cells by 5-O-Benzoylated Taxinine K

Hiroshi Okumura, Zhe-Sheng Chen, Magoichi Sakou, Tomoyuki Sumizawa, Tatsuhiko Furukawa, Masaharu Komatsu, Ryuji Ikeda, Hikokazu Suzuki, Kosaku Hirota, Takashi Aikou, and Shin-Ichi Akiyama

Department of Cancer Chemotherapy, Institute for Cancer Research (H.O., Z.-S.C., T.S., T.F., M.K., R.I., S.-I.A.) First Department of Surgery (T.A.), Kagoshima University School of Medicine, Kagoshima, Japan; and Gifu Pharmaceutical University, Gifu, Japan (M.S., H.S., K.H.)

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 multidrug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (ADM), and vincristine (VCR) of KB-8-5 and KB-C2 cells that overexpress P-gp by directly interacting with P-gp. BTK also moderately reversed the resistance to ADM of KB/MRP cells that overexpress MRP. However, BTK neither inhibited 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 combination with ADM should be useful for treating patients with tumors that overexpress both P-gp and MRP.