Abstract
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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / drug effects
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ATP Binding Cassette Transporter, Subfamily B / metabolism*
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ATP-Binding Cassette Transporters / drug effects
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ATP-Binding Cassette Transporters / metabolism*
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Antineoplastic Agents / pharmacology*
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Azides / metabolism
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Biological Transport / drug effects
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Bridged-Ring Compounds / pharmacology*
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Dihydropyridines / metabolism
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Doxorubicin / pharmacology
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Glutathione / metabolism
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Humans
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KB Cells
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Leukotriene C4 / metabolism
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins / metabolism
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Organelles / drug effects
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Organelles / physiology
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Paclitaxel / pharmacology
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Photoaffinity Labels
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Plants, Medicinal
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Taxoids*
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Taxus / chemistry
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Tritium
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Vault Ribonucleoprotein Particles / metabolism
Substances
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5-O-benzoylated taxinine K
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ATP Binding Cassette Transporter, Subfamily B
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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Azides
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Bridged-Ring Compounds
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Dihydropyridines
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Photoaffinity Labels
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Taxoids
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Vault Ribonucleoprotein Particles
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major vault protein
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Tritium
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Leukotriene C4
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azidopine
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Doxorubicin
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Glutathione
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Paclitaxel