Abstract
Drug resistance in cells is a major impedance to successful treatment of lung cancer. Taxus chinensis var. inhibits the growth of tumor cells and promotes the synthesis of interleukins 1 and 2 and tumor necrosis factor, enhancing immune function. In this study, T. chinensis var.-induced cell death was analyzed in lung cancer cells (H460) enriched for stem cell growth in a defined serum-free medium. Taxus-treated stem cells were also analyzed for Rhodamine 123 (Rh-123) expression by flow cytometry, and used as a standard functional indicator of MDR. The molecular basis of T. chinensis var.-mediated drug resistance was established by real-time PCR analysis of ABCC1, ABCB1, and lung resistance-related protein (LRP) mRNA, and western blot analysis of MRP1, MDR1, and LRP. Our results revealed that stem cells treated with higher doses of T. chinensis var. showed significantly lower growth inhibition rates than did H460 cells (P < 0.05). The growth of stem and H460 cells treated with a combination of T. chinensis var. and cisplatin was also significantly inhibited (P < 0.05). Rh-123 was significantly accumulated in the intracellular region and showed delayed efflux in stem cells treated with T. chinensis var. (P < 0.05), compared to those treated with verapamil. T. chinensis var.-treated stem cells showed significant downregulation of the ABCC1, ABCB1, and LRP mRNA and MRP1, MDR1, and LRP (P < 0.05) compared to H460 cells. Thus, T. chinensis var.-mediated downregulation of MRP1, MDR1, and LRP might contribute to the reversal of drug resistance in non-small cell lung cancer stem cells.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cisplatin / pharmacology
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Drug Combinations
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Drugs, Chinese Herbal
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Gene Expression Regulation, Neoplastic*
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Plant Extracts / chemistry
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Plant Extracts / pharmacology*
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Rhodamine 123 / metabolism
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Signal Transduction
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Taxus / chemistry*
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Vault Ribonucleoprotein Particles / antagonists & inhibitors
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Vault Ribonucleoprotein Particles / genetics
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Vault Ribonucleoprotein Particles / metabolism
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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Antineoplastic Agents
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Drug Combinations
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Drugs, Chinese Herbal
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Multidrug Resistance-Associated Proteins
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Plant Extracts
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Vault Ribonucleoprotein Particles
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major vault protein
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Rhodamine 123
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Cisplatin
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multidrug resistance-associated protein 1