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Combination of siRNA-directed Gene Silencing With Cisplatin Reverses Drug Resistance in Human Non-small Cell Lung Cancer.

ABSTRACT: One of the most challenging aspects of lung cancer therapy is the rapid acquisition of multidrug-resistant (MDR) phenotype. One effective approach would be to identify and downregulate resistance-causing genes in tumors using small interfering RNAs (siRNAs) to increase the sensitivity of tumor cells to chemotherapeutic challenge. After identifying the overexpressed resistance-related antiapoptotic genes (survivin and bcl-2) in cisplatin-resistant cells, the siRNA sequences were designed and screened to select the most efficacious candidates. Modifications were introduced in them to minimize off-target effects. Subsequently, the combination of siRNA and cisplatin that gave the maximum synergy was identified in resistant cells. We then demonstrated that the combination treatment of the selected siRNAs and cisplatin encapsulated in CD44-targeting hyaluronic acid (HA)-based self-assembling nanosystems reversed the resistance to cisplatin and delayed the tumor growth significantly (growth inhibition increased from 30 to 60%) in cisplatin-resistant tumors. In addition, no abnormalities in body weights, liver enzyme levels or histopathology of liver/spleen tissues were observed in any of the treatment groups during the study period. Overall, we demonstrate that the combination of siRNA-mediated gene-silencing strategy with chemotherapeutic agents constitutes a valuable and safe approach for the treatment of MDR tumors.Molecular Therapy-Nucleic Acids (2013) 2, e110; doi:10.1038/mtna.2013.29; published online 30 July 2013.

SUBMITTER: Ganesh S

PROVIDER: S-EPMC3731892 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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Combination of siRNA-directed Gene Silencing With Cisplatin Reverses Drug Resistance in Human Non-small Cell Lung Cancer.

Ganesh Shanthi S Iyer Arun K AK Weiler Jan J Morrissey David V DV Amiji Mansoor M MM

Molecular therapy. Nucleic acids 20130730

One of the most challenging aspects of lung cancer therapy is the rapid acquisition of multidrug-resistant (MDR) phenotype. One effective approach would be to identify and downregulate resistance-causing genes in tumors using small interfering RNAs (siRNAs) to increase the sensitivity of tumor cells to chemotherapeutic challenge. After identifying the overexpressed resistance-related antiapoptotic genes (survivin and bcl-2) in cisplatin-resistant cells, the siRNA sequences were designed and scre ...[more]

PMID: 23900224

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Project description:Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs. We previously developed epidermal growth factor receptor (EGFR)-targeted chitosan (CS) nanoparticles as a versatile delivery system for silencing the essential mitotic checkpoint gene Mad2, and induce cell death. Here, we tested this system as a single therapy and in combination with cisplatin in cisplatin sensitive and resistant lung cancer models, and characterized its in vivo efficacy and safety. Combination treatment resulted in significant improvement in tumor inhibition that was strikingly more effective in cisplatin-resistant tumors. Importantly, effective cisplatin dosage was dramatically reduced in the co-therapy regimen resulting in negligible toxic effects from the drug as confirmed by parameters such as body weight gain, biochemical markers of hepatic and renal function, and histopathology of liver/kidney/spleen tissues. Overall, we demonstrate that the combination of Mad2 siRNA-loaded CS nanoparticles strategy with chemotherapeutic agents such as cisplatin constitutes an efficient and safe approach for the treatment of drug resistant tumors.Statement of significanceLung cancer remains one of the leading killers in the United States and around the world. Platinum agents, including cisplatin, are the first line treatment in lung cancer, including non-small cell lung cancer (NSCLC), which is the predominant form of lung cancer. In this study, we have evaluated Mad2 cell-cycle checkpoint gene silencing using small interfering RNA (siRNA) delivered systemically using epidermal growth factor receptor-targeted chitosan nanoparticles in drug sensitive and resistant models of NSCLC. Our results show that Mad2 gene silencing using targeted chitosan nanoparticles has tremendous potential in overcoming platinum resistance in NSCLC.

Dataset Information

Combination of siRNA-directed Gene Silencing With Cisplatin Reverses Drug Resistance in Human Non-small Cell Lung Cancer.

Publications

Combination of siRNA-directed Gene Silencing With Cisplatin Reverses Drug Resistance in Human Non-small Cell Lung Cancer.

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