Abstract
Overexpression of P-glycoprotein (P-gp), the MDR1 gene product, confers multidrug resistance (MDR) to cancer cells. Clinically, MDR is one of the major causes for chemotherapeutic treatment failure in cancer patients. To explore a new approach to circumventing MDR, we adopted RNA interference to target MDR1 gene expression. RNA interference is a conserved biological response to double-stranded RNA, which results in sequence-specific gene silencing [G. J. Hannon, Nature (Lond.), 418: 244-251, 2002]. We report that introduction of an MDR1-targeted small interfering RNA duplex into drug-resistant cancer cells markedly inhibited the expression of MDR1 mRNA and P-gp, as determined by reverse transcription-PCR and Western blot. Inhibition of P-gp expression by small interfering RNA enhanced the intracellular accumulation of and selectively restored sensitivity to drugs transported by P-gp. These studies indicate that RNA interference can modulate MDR in preclinical models.
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 / antagonists & inhibitors*
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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 / genetics
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Doxorubicin / pharmacokinetics
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Doxorubicin / pharmacology
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Drug Resistance, Multiple / genetics*
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic / genetics
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Genes, MDR / genetics*
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Humans
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Paclitaxel / pharmacokinetics
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Paclitaxel / pharmacology
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics*
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Transfection
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Tumor Cells, Cultured
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Vinblastine / pharmacokinetics
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Vinblastine / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents
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RNA, Small Interfering
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Vinblastine
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Doxorubicin
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Paclitaxel