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Stable and complete overcoming of MDR1/P-glycoprotein-mediated multidrug resistance in human gastric carcinoma cells by RNA interference

Cancer Gene Therapy volume 11, pages 699–706 (2004)Cite this article

Abstract

Multidrug resistance (MDR) is the major cause of failure of effective chemotherapeutic treatment of disseminated neoplasms. The “classical” MDR phenotype of human malignancies is mediated by drug extrusion by the adenosine triphosphate binding cassette (ABC)-transporter P-glycoprotein (MDR1/P-gp). For stable reversal of “classical” MDR by RNA interference (RNAi) technology, an H1-RNA gene promoter-driven expression vector encoding anti-MDR1/P-gp short hairpin RNA (shRNA) molecules was constructed. By introduction of anti-MDR1/P-gp shRNA expression vectors into the extremely high drug-resistant human gastric carcinoma cell line EPG85-257RDB, the MDR phenotype was completely reversed. The reversal of MDR was accompanied by a complete suppression of MDR1/P-gp expression on mRNA and protein level, and by a considerable increased intracellular anthracyline accumulation in the anti-MDR1/P-gp shRNA-treated cells. The data indicate that stable shRNA-mediated RNAi can be tremendously effective in reversing MDR1/P-gp-mediated MDR and is therefore a promising strategy for overcoming MDR by gene therapeutic applications.

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Acknowledgements

This work was supported by Grant LA 1039/2-3 of the “Deutsche Forschungsgemeinschaft” (DFG) and by the “RNA-network” funded by the “Bundesministerium für Bildung und Forschung” (BMBF) and Berlin.

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  1. Charité Campus Mitte, Institute of Pathology, Schumannstr. 20/21, Berlin, D-10117, Germany

    Alexandra Stege, Axel Priebsch, Christiane Nieth & Hermann Lage

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  1. Alexandra Stege
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  2. Axel Priebsch
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  3. Christiane Nieth
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  4. Hermann Lage
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Correspondence to Hermann Lage.

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Stege, A., Priebsch, A., Nieth, C. et al. Stable and complete overcoming of MDR1/P-glycoprotein-mediated multidrug resistance in human gastric carcinoma cells by RNA interference. Cancer Gene Ther 11, 699–706 (2004). https://doi.org/10.1038/sj.cgt.7700751

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