title: Effect of siRNA pre-Exposure on Subsequent Response to siRNA Therapy.
abstract: OBJECTIVE
  An alternative cancer therapy based on RNA interference (RNAi) has shown considerable promise but the possibility of resistance development is not known. This study explored the possibility of therapeutic resistance against siRNA nanoparticles in human cancer cells.
  
  
  METHODS
  Two approaches to siRNA treatment were undertaken using lipid-modified polyethylenimines, a single high concentration (shock) and repeated increasing concentrations (gradual). The targets were Mcl-1, RPS6KA5 and KSP in MDA-MB-435 cells.
  
  
  RESULTS
  There was no evidence of resistance development in shock-treated cells, while the decrease in mRNA levels of targeted proteins was not as robust in naïve cells in gradual treatment. However, silencing efficiency was restored after a 7-day recovery period when expression of suppressed proteins returned to normal levels. Cellular uptake of siRNA was not affected by pre-treatments. Other mediators involved in cell survival and proliferation were altered in siRNA-treated cells, but only JUN silencing led to a heightened loss of viability. In vivo experiments demonstrated similar silencing efficiency at mRNA level after repeat doses.
  
  
  CONCLUSIONS
  Human cancer cells responded to repeat siRNA nanoparticles in a similar fashion after a temporary initial alteration and little, if any, resistance was evident against repeated siRNA treatments.
authors.affiliation: School of Pharmacy, Chapman University, #211, 9401 Jeronimo Road, Irvine, California, 92618, USA. montazer@chapman.edu.|Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, #2-020 RTF, Edmonton, Alberta, T6G 2G6, Canada. montazer@chapman.edu.
authors.forename: Hamidreza Montazeri
authors.initials: HM
authors.lastname: Aliabadi
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, #2-020 RTF, Edmonton, Alberta, T6G 2G6, Canada.
authors.forename: Parvin
authors.initials: P
authors.lastname: Mahdipoor
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, #2-020 RTF, Edmonton, Alberta, T6G 2G6, Canada.
authors.forename: Cezary
authors.initials: C
authors.lastname: Kucharsky
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, #2-020 RTF, Edmonton, Alberta, T6G 2G6, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Chan
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, #2-020 RTF, Edmonton, Alberta, T6G 2G6, Canada. huludag@ualberta.ca.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada. huludag@ualberta.ca.|Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada. huludag@ualberta.ca.
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D000067492:RNAi Therapeutics / Q000379:methods*
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D011094:Polyethyleneimine
keywords: cancer therapy; polymeric carriers; resistance; siRNA