In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells.
<h4>Background & aim</h4>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 upregul...
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Public Library of Science (PLoS)
2014-01-01
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| author | Maria Teresa Di Martino Annamaria Gullà Maria Eugenia Gallo Cantafio Emanuela Altomare Nicola Amodio Emanuela Leone Eugenio Morelli Santo Giovanni Lio Daniele Caracciolo Marco Rossi Niels M Frandsen Pierosandro Tagliaferri Pierfrancesco Tassone |
| author_facet | Maria Teresa Di Martino Annamaria Gullà Maria Eugenia Gallo Cantafio Emanuela Altomare Nicola Amodio Emanuela Leone Eugenio Morelli Santo Giovanni Lio Daniele Caracciolo Marco Rossi Niels M Frandsen Pierosandro Tagliaferri Pierfrancesco Tassone |
| author_sort | Maria Teresa Di Martino |
| collection | DOAJ |
| description | <h4>Background & aim</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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. |
| format | Article |
| id | doaj-art-5984928a680a45cda3695ce3ebba0d15 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-5984928a680a45cda3695ce3ebba0d152025-08-20T03:01:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8965910.1371/journal.pone.0089659In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells.Maria Teresa Di MartinoAnnamaria GullàMaria Eugenia Gallo CantafioEmanuela AltomareNicola AmodioEmanuela LeoneEugenio MorelliSanto Giovanni LioDaniele CaraccioloMarco RossiNiels M FrandsenPierosandro TagliaferriPierfrancesco Tassone<h4>Background & aim</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089659&type=printable |
| spellingShingle | Maria Teresa Di Martino Annamaria Gullà Maria Eugenia Gallo Cantafio Emanuela Altomare Nicola Amodio Emanuela Leone Eugenio Morelli Santo Giovanni Lio Daniele Caracciolo Marco Rossi Niels M Frandsen Pierosandro Tagliaferri Pierfrancesco Tassone In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells. PLoS ONE |
| title | In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells. |
| title_full | In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells. |
| title_fullStr | In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells. |
| title_full_unstemmed | In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells. |
| title_short | In vitro and in vivo activity of a novel locked nucleic acid (LNA)-inhibitor-miR-221 against multiple myeloma cells. |
| title_sort | in vitro and in vivo activity of a novel locked nucleic acid lna inhibitor mir 221 against multiple myeloma cells |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089659&type=printable |
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