title: In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma.
abstract: Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are urgently awaited. A rising body of evidence supports the notion that microRNAs (miRNAs), master regulators of eukaryotic gene expression, may exert anti-MM activity. Here, we evaluated the activity of synthetic miR-34a in MM cells. We found that transfection of miR-34a mimics in MM cells induces a significant change of gene expression with relevant effects on multiple signal transduction pathways. We detected early inactivation of pro-survival and proliferative kinases Erk-2 and Akt followed at later time points by caspase-6 and -3 activation and apoptosis induction. To improve the in vivo delivery, we encapsulated miR-34a mimics in stable nucleic acid lipid particles (SNALPs). We found that SNALPs miR-34a were highly efficient in vitro in inhibiting growth of MM cells. Then, we investigated the activity of the SNALPs miR-34a against MM xenografts in SCID mice. We observed significant tumor growth inhibition (p<0.05) which translated in mice survival benefits (p=0.0047). Analysis of miR-34a and NOTCH1 expression in tumor retrieved from animal demonstrated efficient delivery and gene modulation induced by SNALPs miR-34a in the absence of systemic toxicity. We here therefore provide evidence that SNALPs miR-34a may represent a promising tool for miRNA-therapeutics in MM.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Catanzaro, Italy ; T. Campanella Cancer Center, "Salvatore Venuta" University Campus, Catanzaro, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.affiliation: Department of Pharmacy, Federico II University of Naples, Naples, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Campani
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Misso
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Catanzaro, Italy.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Gallo Cantafio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Catanzaro, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gullà
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Catanzaro, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Foresta
authors.affiliation: Department of Medical and Surgical Sciences, Laboratory of Bioinformatics Unit, "Salvatore Venuta" University Campus, Catanzaro, Italy.
authors.forename: Pietro Hiram
authors.initials: PH
authors.lastname: Guzzi
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Castellano
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Grimaldi
authors.affiliation: Pathology Unit, National Institute of Tumours of Naples "Pascale", Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Gigantino
authors.affiliation: Pathology Unit, National Institute of Tumours of Naples "Pascale", Naples, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.affiliation: Department of Pharmacy, Federico II University of Naples, Naples, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lusa
authors.affiliation: Department of Medical and Surgical Sciences, Laboratory of Bioinformatics Unit, "Salvatore Venuta" University Campus, Catanzaro, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cannataro
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Catanzaro, Italy ; T. Campanella Cancer Center, "Salvatore Venuta" University Campus, Catanzaro, Italy.
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Department of Pharmacy, Federico II University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Rosa
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Catanzaro, Italy ; T. Campanella Cancer Center, "Salvatore Venuta" University Campus, Catanzaro, Italy ; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy ; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases