title: Induction of apoptosis by survivin silencing through siRNA delivery in a human breast cancer cell line.
abstract: Post-transcriptional silencing of antiapoptotic genes is a promising strategy for cancer therapy, but delivering short interfering RNA (siRNA) molecules against such targets is challenging due to inability of anionic siRNA to cross cellular membranes. Lipid substitution on small molecular weight, nontoxic polyethylenimine (PEI) has been investigated as a promising approach for effective siRNA delivery. In this study, we report on the ability of low molecular weight, lipid-substituted PEI to deliver siRNA against the antiapoptotic protein survivin. Toxicity of a library of lipid-substituted PEIs, as well as their siRNA delivery and survivin silencing efficiency, was evaluated in MDA-MB-231 human breast cancer cells. A significant increase in cellular delivery of siRNA was observed as a result of lipid substitution. Most significant downregulation of survivin was established by caprylic acid-substituted polymers, which resulted in significant levels of apoptosis induction and resultant loss of cell viability. Survivin downregulation prior to anticancer drug treatment decreased the IC(50) of several drugs by 50- to 120-fold. Our experiments indicated an effective downregulation of survivin, a cell protective protein upregulated in tumor cells, by delivering siRNA with hydrophobically modified PEI. This study introduces a promising delivery system for safe and effective siRNA delivery that will be suitable for further investigation in preclinical animal models.
authors.affiliation: Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Montazeri Aliabadi
authors.forename: Breanne
authors.initials: B
authors.lastname: Landry
authors.forename: Parvin
authors.initials: P
authors.lastname: Mahdipoor
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D000970:Antineoplastic Agents / Q000819:agonists / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002210:Caprylates / Q000737:chemistry; D045744:Cell Line, Tumor; D053144:Cell Nucleus Shape; D002470:Cell Survival / Q000187:drug effects; D005240:Feasibility Studies; D005260:Female; D020868:Gene Silencing; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007097:Imines / Q000009:adverse effects / Q000737:chemistry; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020128:Inhibitory Concentration 50; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010316:Particle Size; D011095:Polyethylenes / Q000009:adverse effects / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000378:metabolism*; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002210:Caprylates; D007097:Imines; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D011095:Polyethylenes; D034741:RNA, Small Interfering; D000077022:Survivin; C505405:poly(ethylene imine); C031492:octanoic acid