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Double siRNA-targeting of cIAP2 and LIVIN results in synergetic sensitization of HCT-116 cells to oxaliplatin treatment
Authors Bavykin AS, Korotaeva AA, Poyarkov SV, Syrtsev AV, Tjulandin SA, Karpukhin AV
Received 7 March 2013
Accepted for publication 14 May 2013
Published 23 September 2013 Volume 2013:6 Pages 1333—1340
DOI https://doi.org/10.2147/OTT.S44893
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Andrey S Bavykin,1 Alexandra A Korotaeva,1 Stanislav V Poyarkov,2 Alexandr V Syrtsev,1,3 Sergei A Tjulandin,3 Alexandr V Karpukhin1
1Russian Academy of Medical Science Research Centre for Medical Genetics, Moscow, Russian Federation; 2D.I. Ivanovsky Institute of Virology Russian Academy of Medical Sciences, Moscow, Russian Federation; 3N.N. Blokhin Russian Cancer Research Center under the Russian Academy of Medical Sciences; Moscow, Russian Federation
Purpose: Most colon cancers show low sensitivity to treatment with oxaliplatin and a specific strategy is needed to overcome this problem. Our approach uses RNA interference to silence the expression of target genes responsible for the development of oxaliplatin resistance. Profile analysis of genes related to the regulation of apoptosis allowed identification of target genes showing the greatest degree of upregulation in response to oxaliplatin exposure.
Methods: We designed a panel of genes with functions closely related to inactivation of the caspase cascade, endoplasmic reticulum stress reduction, and drug metabolism. The candidate genes were silenced by means of specific small interfering RNA (siRNA) oligonucleotides.
Results: The caspase 3 and 9 inhibitors of apoptosis 2 (cIAP2) and LIVIN were found to be the most dose-responsive genes during the period of oxaliplatin treatment. Two-fold sensitization of cells to oxaliplatin was observed with independent knockdown of either cIAP2 or LIVIN expression. siRNA-silencing of both targets produced a five-fold increase in oxaliplatin sensitivity of HCT-116 cells.
Conclusion: A dose-dependent approach revealed reliable targets for siRNA-silencing under low doses of oxaliplatin. Targeting the key proapoptotic chain with several specific siRNAs resulted in synergetic sensitization of HCT-116 cells to oxaliplatin treatment.
Keywords: drug resistance, inhibition of apoptosis, RNA interference
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