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PLoS One. 2014 Feb 21;9(2):e89659. doi: 10.1371/journal.pone.0089659. eCollection 2014.

In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells.

Author information

1
Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy ; T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy.
2
Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy.
3
Pathology Unit, "Giovanni Paolo II" Hospital, Lamezia Terme, Catanzaro, Italy.
4
Exiqon A/S, Vedbaek, Denmark.
5
Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, Salvatore Venuta University Campus, 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.

Abstract

BACKGROUND & AIM:

The miR-221/222 cluster is upregulated in malignant plasma cells from multiple myeloma (MM) patients harboring the t(4;14) translocation. We previously reported that silencing of miR-221/222 by an antisense oligonucleotide induces anti-MM activity and upregulates canonical miR-221/222 targets. The in vivo anti-tumor activity occurred when miR-221/222 inhibitors were delivered directly into MM xenografts. The aim of the present study was to evaluate the anti-MM activity of a novel phosphorothioate modified backbone 13-mer locked nucleic acid (LNA)-Inhibitor-miR-221 (LNA-i-miR-221) specifically designed for systemic delivery.

METHODS:

In vitro anti-MM activity of LNA-i-miR-221 was evaluated by cell proliferation and BrdU uptake assays. In vivo studies were performed with non-obese diabetic/severe combined immunodeficient (NOD.SCID) mice bearing t(4;14) MM xenografts, which were intraperitoneally or intravenously treated with naked LNA-i-miR-221. RNA extracts from retrieved tumors were analyzed for miR-221 levels and modulation of canonical targets expression. H&E staining and immunohistochemistry were performed on retrieved tumors and mouse vital organs.

RESULTS:

In vitro, LNA-i-miR-221 exerted strong antagonistic activity against miR-221 and induced upregulation of the endogenous target p27Kip1. It had a marked anti-proliferative effect on t(4;14)-translocated MM cells but not on MM cells not carrying the translocation and not overexpressing miR-221. In vivo, systemic treatment with LNA-i-miR-221 triggered significant anti-tumor activity against t(4;14) MM xenografts; it also induced miR-221 downregulation, upregulated p27Kip1 and reduced Ki-67. No behavioral changes or organ-related toxicity were observed in mice as a consequence of treatments.

CONCLUSIONS:

LNA-i-miR-221 is a highly stable, effective agent against t(4;14) MM cells, and is suitable for systemic use. These data provide the rationale for the clinical development of LNA-i-miR-221 for the treatment of MM.

PMID:
24586944
PMCID:
PMC3931823
DOI:
10.1371/journal.pone.0089659
[Indexed for MEDLINE]
Free PMC Article

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