title: Effective down-regulation of signal transducer and activator of transcription 3 (STAT3) by polyplexes of siRNA and lipid-substituted polyethyleneimine for sensitization of breast tumor cells to conventional chemotherapy.
abstract: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a major role in the development of resistance to conventional anti-cancer drugs in many types of cancer, when constitutively activated. Inhibition of STAT3 is considered as a promising strategy for inhibition of tumor growth and overcoming the drug resistance manifested. In this study, the capability of STAT3 knockdown by lipid substituted low molecular weight (2 kDa) polyethyleneimine (PEI2) complexes of STAT3-siRNA was assessed. The efficiency of PEI/STAT3-siRNA polyplexes in the induction of STAT3 associated cell death in wild type and drug-resistant MDA-MB-435 breast cancer cells as monotherapy and upon combination with chemotherapeutic agents, doxorubicin and paclitaxel, was also investigated. Our results identified linoleic acid-substituted (PEI-LA) polymer as the most efficient carrier among different lipid substituted PEI2 for siRNA delivery, leading to most STAT3 associated loss of cell viability in MDA-MB-435 cells. STAT3-siRNA delivery by the PEI-LA polymer resulted in efficient down-regulation of STAT3 at both mRNA and protein levels. Furthermore, pre-treatment of cancer cells with STAT3-siRNA formulation increased the cytotoxic effect of doxorubicin and paclitaxel in both wild type and drug resistant MDA-MB-435 cells. The results of this study point to the potential of PEI-LA polyplexes of STAT3-siRNA as inhibitors of STAT3 expression in breast tumor cells. The results also demonstrate an improved efficacy for chemotherapeutic drugs in combination with lipid-substituted low molecular weight PEI-LA/STAT3-siRNA complexes in comparison to drug therapy alone.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Arash
authors.initials: A
authors.lastname: Falamarzian
authors.forename: Hamidreza Montazeri
authors.initials: HM
authors.lastname: Aliabadi
authors.forename: Ommoleila
authors.initials: O
authors.lastname: Molavi
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D017239:Paclitaxel / Q000627:therapeutic use; D011094:Polyethyleneimine / Q000031:analogs & derivatives*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D004317:Doxorubicin; D011094:Polyethyleneimine; D017239:Paclitaxel
keywords: STAT3; chemotherapy; hydrophobic modification; polycationic polymers; siRNA