Abstract
Multidrug resistance following initial chemotherapy is commonly associated with MDR1 gene encoding for P-glycoprotein (P-gp). RNA interference of MDR1 gene expression was used as a strategy to reverse MDR1-mediated multidrug resistance phenotypes. Here we report that endonuclease-prepared small interfering RNA (esiRNA) at concentrations as low as 10 ng/ml (about 0.7 nM) can decrease MDR1 expression and increase chemosensitivity in the Adriamycin-induced resistant MCF-7/R cells. When MCF-7/R cells were transiently transfected with esiRNA of MDR1 (esiMDR1), the MDR1 mRNA was reduced by about 50%, drug accumulation increased by about 30%, and the IC50 for daunorubicin was reduced from 4.5 to 1.2 microM. These results provide evidence that esiRNA of MDR1 could be an alternative to P-gp inhibitors with the advantage of avoiding non-specific suppression with a lower effective dosage than using a single siRNA duplex, offering a potential therapeutic application of siRNA.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
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Animals
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Antibiotics, Antineoplastic / pharmacology
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CHO Cells
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cricetinae
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Cricetulus
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Daunorubicin / pharmacology
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Dose-Response Relationship, Drug
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Down-Regulation / genetics
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Drug Resistance, Neoplasm / genetics*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Plasmids / genetics
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RNA Interference*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics*
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RNA, Small Interfering / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Rhodamine 123 / metabolism
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Rhodamine 123 / pharmacokinetics
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Ribonuclease III / metabolism
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Transfection
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antibiotics, Antineoplastic
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RNA, Messenger
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Green Fluorescent Proteins
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Rhodamine 123
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Ribonuclease III
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Daunorubicin