Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice
| Autor: | Iran Tavakoli, Anna Fronda, Kevin McClintock, Lina Hu, Adam Judge, Jasna Levi, Ellen Grace Ambegia, Marjorie Robbins, Ian MacLachlan |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cell Death
Cell Survival Stable nucleic acid lipid particle RNA Cancer General Medicine Genetic Therapy Neoplasms Experimental Biology medicine.disease PLK1 Neoplasm genetics Mice Mechanism of action Technical Advance RNA interference medicine Cancer research Experimental pathology Animals medicine.symptom RNA Small Interfering |
| Popis: | siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target’s biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics. |
| Databáze: | OpenAIRE |
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