Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: In vitro and in vivo evidence
Articolo
Data di Pubblicazione:
2012
Abstract:
Purpose: Deregulated expression of miRNAs has been shown 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 miR-34a-stable enforced expression 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 severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional 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. ©2012 AACR.
Tipologia CRIS:
03A-Articolo su Rivista
Elenco autori:
Di Martino M.T.; Leone E.; Amodio N.; Foresta U.; Lionetti M.; Pitari M.R.; Gallo Cantafio M.E.; Gulla A.; Conforti F.; Morelli E.; Tomaino V.; Rossi M.; Negrini M.; Ferrarini M.; Caraglia M.; Shammas M.A.; Munshi N.C.; Anderson K.C.; Neri A.; Tagliaferri P.; Tassone P.
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