title: 5'-Triphosphate siRNA targeting MDR1 reverses multi-drug resistance and activates RIG-I-induced immune-stimulatory and apoptotic effects against human myeloid leukaemia cells.
abstract: Multi-drug resistance (MDR), immune suppression and decreased apoptosis are important causes of therapy-failure in leukaemia. Short interfering RNAs (siRNAs) down-regulate gene transcription, have sequence-independent immune-stimulatory effects and synergize with other anti-cancer therapies in some experimental models. We designed a siRNA targeting MDR1 with 5'-triphosphate ends (3p-siRNA-MDR1). Treatment of leukaemia cells with 3p-siRNA-MDR1 down-regulated MDR1 expression, reduced-drug resistance and induced immune and pro-apoptotic effects in drug-resistant HL-60/Adr and K562/Adr human leukaemia cell lines. We show mechanisms-of-action of these effects involve alterations in the anti-viral cytosolic retinoic acid-inducible protein-I (RIG-I; encoded by RIG-I or DDX58) mediated type-I interferon signal induction, interferon-gamma-inducible protein 10 (IP-10; encoded by IP10 or CXCL10) secretion, major histocompatibility complex-I expression (MHC-I) and caspase-mediated cell apoptosis. 3p-siRNA-MDR1 transfection also enhanced the anti-leukaemia efficacy of doxorubicin. These data suggest a possible synergistic role for 3p-siRNA-MDR1 in anti-leukaemia therapy.
authors.affiliation: Department of Haematology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Dengzhe
authors.initials: D
authors.lastname: Li
authors.affiliation: Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London SW72AZ, UK.
authors.forename: Robert Peter
authors.initials: RP
authors.lastname: Gale
authors.affiliation: Department of Haematology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Haematology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Baoxia
authors.initials: B
authors.lastname: Lei
authors.affiliation: Department of Haematology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery Oncology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Diao
authors.affiliation: Department of Haematology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: zhangmei_xjtu@hotmail.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D007951:Leukemia, Myeloid; D034741:RNA, Small Interfering / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C437968:PLAAT4 protein, human; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid
keywords: CXCL10; DDX58; MDR1; RIG-I; apoptosis; leukaemia; siRNA