Abstract
PurposeMost 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.MethodsWe 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.ResultsThe 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.ConclusionA 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.
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