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Combination of siRNA-directed gene silencing with cisplatin reverses drug resistance in human non-small cell lung cancer

Ganesh, S and Iyer, AK and Weiler, J and Morrissey, DV and Amiji, MM (2013) Combination of siRNA-directed gene silencing with cisplatin reverses drug resistance in human non-small cell lung cancer. Molecular Therapy - Nucleic Acids.

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. 2013 The American Society of Gene & Cell Therapy All rights reserved

Item Type: Article
Additional Information: pubid: 49 nvp_institute: NIBR contributor_address: (Ganesh, Iyer, Amiji) Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, 140 The Fenway, R156, Boston, MA 02115, United States (Ganesh, Weiler, Morrissey) Novartis Institutes for Biomedical Research Inc., Cambridge, MA, United States
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21897

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