Abstract
Taxol treatment froze the cell cycle in the G(2)/M phase, induced morphological changes characteristic of apoptotic/necrotic cell death and increased CYP3A4 enzymatic activity, CYP3A4 mRNA and protein levels in HepG2 cells overexpressing CYP3A4. Apoptosis was associated with cytochrome c release to the cytosol; however, at higher Taxol levels, cells became relatively resistant to the drug-induced freezing of the cell cycle and saturation thresholds for both antiproliferative and proapoptotic activity of Taxol were observed. P-Glycoprotein expression was only slightly increased by Taxol, however, P-glycoprotein-mediated pumping efficiency was significantly increased. Preincubation of cells with an anti-MDR1 monoclonal antibody prior to the drug treatment, coincubation of cells with a potent CYP3A4 inhibitor--ketoconazole--or with both compounds increased Taxol toxicity and proapoptotic activity, indicating that the P-glycoprotein system has a major role in Taxol disposition in hepatoblastoma cells.
Copyright 2003 S. Karger AG, Basel
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Antineoplastic Agents, Phytogenic / administration & dosage
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / biosynthesis*
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Cytochrome P-450 Enzyme System / genetics
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Cytochromes c / metabolism
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Dose-Response Relationship, Drug
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Hepatoblastoma
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Humans
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Ketoconazole / pharmacology
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Necrosis
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Paclitaxel / administration & dosage
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Paclitaxel / pharmacology*
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RNA, Messenger / biosynthesis
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents, Phytogenic
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Carrier Proteins
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Cytochrome P-450 Enzyme Inhibitors
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RNA, Messenger
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Cytochromes c
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Cytochrome P-450 Enzyme System
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Paclitaxel
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Ketoconazole