Abstract
A newly synthesized taxoid originally from the Japanese yewTaxus 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.
Footnotes
- Received July 17, 2000.
- Accepted September 13, 2000.
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Send reprint requests to: Dr. Shin-ichi Akiyama, Department of Cancer Chemotherapy, Institute for Cancer Research, Faculity of Medicine, Kagoshima University, 8–35-1 Sakuragaoka Kagoshima 890-8520, Japan. E-mail:akiyamas{at}m3.kufm.kagoshima-u.ac.jp
- The American Society for Pharmacology and Experimental Therapeutics
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