title: 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.
authors.affiliation: 1] Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA [2] Novartis Institutes for Biomedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Ganesh
authors.forename: Arun K
authors.initials: AK
authors.lastname: Iyer
authors.forename: Jan
authors.initials: J
authors.lastname: Weiler
authors.forename: David V
authors.initials: DV
authors.lastname: Morrissey
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
references.citation: Drug Discov Today. 2006 Sep;11(17-18):812-8
references.pmid: 16935749
references.citation: Pharm Res. 2003 Mar;20(3):351-9
references.pmid: 12669953
references.citation: Curr Pharm Des. 2006;12(3):273-86
references.pmid: 16454744
references.citation: Nat Rev Cancer. 2002 Jan;2(1):48-58
references.pmid: 11902585
references.citation: Nat Biotechnol. 2005 Aug;23(8):995-1001
references.pmid: 16025102
references.citation: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2008 Jun;152(1):47-51
references.pmid: 18795074
references.citation: Biomaterials. 2013 Apr;34(13):3489-502
references.pmid: 23410679
references.citation: Ann Oncol. 1999;10 Suppl 5:S83-6
references.pmid: 10582146
references.citation: Gut. 2005 Sep;54(9):1298-308
references.pmid: 16099798
references.citation: Gene Ther. 2004 Jul;11(14):1170-4
references.pmid: 15164094
references.citation: Acta Biochim Biophys Sin (Shanghai). 2007 Nov;39(11):835-43
references.pmid: 17989874
references.citation: Clin Exp Pharmacol Physiol. 2007 May-Jun;34(5-6):450-6
references.pmid: 17439414
references.citation: J Control Release. 2000 Mar 1;65(1-2):271-84
references.pmid: 10699287
references.citation: Curr Drug Targets. 2004 May;5(4):389-406
references.pmid: 15134222
references.citation: Science. 1992 Dec 4;258(5088):1650-4
references.pmid: 1360704
references.citation: Mol Ther. 2011 May;19(5):928-35
references.pmid: 21364537
references.citation: Clin Cancer Res. 2005 Jun 15;11(12):4487-94
references.pmid: 15958634
references.citation: Nanomedicine (Lond). 2008 Dec;3(6):761-76
references.pmid: 19025451
references.citation: J Control Release. 2010 Sep 1;146(2):219-27
references.pmid: 20403397
references.citation: Mol Pharm. 2011 Aug 1;8(4):1120-31
references.pmid: 21619051
references.citation: Acta Biochim Biophys Sin (Shanghai). 2009 Mar;41(3):223-30
references.pmid: 19280061
references.citation: Cancer Res. 2004 Sep 1;64(17):6214-24
references.pmid: 15342407
references.citation: Cancer Immunol Immunother. 2004 Mar;53(3):153-9
references.pmid: 14749900
references.citation: Clin Cancer Res. 2008 Mar 1;14(5):1310-6
references.pmid: 18316549