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  • Title: Modulation of MDR1 gene expression in multidrug resistant MCF7 cells by low concentrations of small interfering RNAs.
    Author: Stierlé V, Laigle A, Jollès B.
    Journal: Biochem Pharmacol; 2005 Nov 15; 70(10):1424-30. PubMed ID: 16214115.
    Abstract:
    MDR1 overexpression is one form of the multidrug resistance (MDR) phenotype, which can be acquired by patients initially responsive to chemotherapy. Because of the high toxicity of the inhibitors of P-glycoprotein (P-gp), the protein encoded by MDR1, attention has been focused on selective modulation of the MDR1 gene. Small interfering RNAs (siRNAs) were shown to be powerful tools for such a purpose, even when used at low concentrations (< or =20 nM) in order to avoid sequence nonspecific effects. Two siRNAs used at 20 nM were shown to lead to efficient down-regulation of MDR1 at the protein level (only ca. 20% total P-gp expression remaining) in the doxorubicin selected MCF7-R human cell line. Cell surface expression of P-gp was inhibited, leading to reversal of the drug efflux phenotype (about 40% reversal with the most efficient siRNA) and enhancement of chemosensitivity (about 35%). At the mRNA level, the down-regulation of MDR1 obtained with the most efficient siRNA increased from about 50% (5 nM siRNA) to 60% (10 or 20 nM). The advantage of using a combination of siRNAs instead of a single one has been suggested.
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