Document Detail


Synthetic miR-34a mimics as a novel therapeutic agent for Multiple Myeloma: in vitro and in vivo evidence.
MedLine Citation:
PMID:  23035210     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PURPOSE: Deregulated expression of microRNAs (miRNAs) has been demonstrated in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a EXPERIMENTAL DESIGN: Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo RESULTS: Either transient expression of miR-34a synthetic mimics or lentivirus-based stable enforced expression of miR-34a gene triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6 and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in SCID mice. The anti-MM activity of lipidic-formulated miR-34a was further demonstrated in vivo in two different experimental settings: i) SCID mice bearing non transduced MM xenografts; and ii) SCID-synth-hu mice implanted with synthetic 3D scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity CONCLUSIONS: Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.
Authors:
Maria T Di Martino; Emanuela Leone; Nicola Amodio; Umberto Foresta; Marta Lionetti; Maria Rita Pitari; Maria E Gallo Cantafio; Annamaria Gullà; Francesco Conforti; Eugenio Morelli; Vera Tomaino; Marco Rossi; Massimo Negrini; Manlio Ferrarini; Michele Caraglia; Masood A Shammas; Nikhil C Munshi; Kenneth C Anderson; Antonino Neri; Pierosandro Tagliaferri; Pierfrancesco Tassone
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-3
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  -     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Medical Oncology Unit, University Magna Graecia.
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