Suppression of MDR1 gene expression by chemically modified siRNAs |
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Authors: | E. B. Logashenko A. V. Vladimirova A. A. Volkov M. N. Repkova A. G. Ven’yaminova M. A. Zenkova E. L. Chernolovskaya V. V. Vlassov |
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Affiliation: | (1) Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy or Sciences, 8 prosp. Akad. Lavrent’eva, 630090 Novosibirsk, Russian Federation |
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Abstract: | The ability of chemically modified siRNAs targeted to MDR1 mRNA to inhibit P-glycoprotein expression and to restore sensitivity of cancer cells to antibiotic vinblastine was investigated. The effects of chemical modifications on RNA stability in cell culture medium and inhibition of MDR1 gene expression were tested. We found that siRNAs containing 2′-O-methyl ribonucleotides within either sense or/and antisense strands display high stability in serum but exhibit a significant reduction in the biological activity. The protection of 3′-ends of siRNA by introduction of 3′-3′-inverted phosphodiester bonds and two 2′-O-methyl ribonucleotides in protruding 3′-ends considerably increase their biological activity, which allows a 30-fold decrease in the cytostatic agent concentration required for cancer cell death. The data obtained demonstrate that the chemically modified siRNAs can be considered as potential therapeutics, which enhances the efficiency of cancer chemotherapy. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1227–1235, July, 2006. |
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Keywords: | RNA interference siRNA dsRNA P-glycoprotein MDR1 multidrug resistance |
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