Abstract
Mitochondrial DNA-depleted ρ0 cells are resistant to apoptosis, but the mechanism remains unclear. A human hepatoma cell line (SK-Hep1) depleted of mtDNA (ρ0SK-Hep1) was induced by ethidium bromide treatment. The ρ0SK-Hep1 cells were resistant to both doxorubicin- and cisplatin-induced apoptosis, while cybrids (SK-Hep1Cyb) prepared by fusing ρ0SK-Hep1 cells with platelets showed restored susceptibility to both drugs. We observed P-glycoprotein and MRP1 were both overexpressed in ρ0 cells, and more P-glycoproteins were localized in the mitochondria and were functionally active. ρ0 cells showed resistance to chemotherapeutic drug-induced apoptosis. The increased expression and localization of P-glycoproteins in the mitochondria of ρ0 cells may facilitate the exclusion of chemotherapeutic drugs from the mitochondria to the cytosol.
Publication types
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Research Support, Non-U.S. Gov't
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 / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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DNA, Mitochondrial / genetics
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DNA, Mitochondrial / metabolism*
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Doxorubicin / pharmacology
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Flow Cytometry
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Humans
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Membrane Potential, Mitochondrial
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Microscopy, Fluorescence
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Mitochondria, Liver / metabolism*
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Multidrug Resistance-Associated Proteins / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Reactive Oxygen Species / metabolism
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bcl-2-Associated X Protein / biosynthesis
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents
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BAX protein, human
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DNA, Mitochondrial
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Multidrug Resistance-Associated Proteins
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Proto-Oncogene Proteins c-bcl-2
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Reactive Oxygen Species
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bcl-2-Associated X Protein
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Doxorubicin
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multidrug resistance-associated protein 1