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 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.
Okumura
H
H
Department of Cancer Chemotherapy, Institute for Cancer Research, Kagoshima University School of Medicine, Kagoshima, Japan.
Chen
Z S
ZS
Sakou
M
M
Sumizawa
T
T
Furukawa
T
T
Komatsu
M
M
Ikeda
R
R
Suzuki
H
H
Hirota
K
K
Aikou
T
T
Akiyama
S I
SI
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001386:Azides / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007624:KB Cells; D017997:Leukotriene C4 / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D019920:Photoaffinity Labels; D010946:Plants, Medicinal; D043823:Taxoids; D020946:Taxus / Q000737:chemistry; D014316:Tritium; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism; D000099187:Major Vault Protein
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001386:Azides; D001952:Bridged-Ring Compounds; D004095:Dihydropyridines; D004317:Doxorubicin; D005978:Glutathione; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D019920:Photoaffinity Labels; D043823:Taxoids; D014316:Tritium; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C418044:5-O-benzoylated taxinine K; C041130:azidopine