Cargando…
In Vitro and In Vivo Activity of a Novel Locked Nucleic Acid (LNA)-Inhibitor-miR-221 against Multiple Myeloma Cells
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-...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931823/ https://www.ncbi.nlm.nih.gov/pubmed/24586944 http://dx.doi.org/10.1371/journal.pone.0089659 |
_version_ | 1782304720727048192 |
---|---|
author | Di Martino, Maria Teresa Gullà, Annamaria Gallo Cantafio, Maria Eugenia Altomare, Emanuela Amodio, Nicola Leone, Emanuela Morelli, Eugenio Lio, Santo Giovanni Caracciolo, Daniele Rossi, Marco Frandsen, Niels M. Tagliaferri, Pierosandro Tassone, Pierfrancesco |
author_facet | Di Martino, Maria Teresa Gullà, Annamaria Gallo Cantafio, Maria Eugenia Altomare, Emanuela Amodio, Nicola Leone, Emanuela Morelli, Eugenio Lio, Santo Giovanni Caracciolo, Daniele Rossi, Marco Frandsen, Niels M. Tagliaferri, Pierosandro Tassone, Pierfrancesco |
author_sort | Di Martino, Maria Teresa |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3931823 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39318232014-02-25 In Vitro and In Vivo Activity of a Novel Locked Nucleic Acid (LNA)-Inhibitor-miR-221 against Multiple Myeloma Cells Di Martino, Maria Teresa Gullà, Annamaria Gallo Cantafio, Maria Eugenia Altomare, Emanuela Amodio, Nicola Leone, Emanuela Morelli, Eugenio Lio, Santo Giovanni Caracciolo, Daniele Rossi, Marco Frandsen, Niels M. Tagliaferri, Pierosandro Tassone, Pierfrancesco PLoS One Research Article 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. Public Library of Science 2014-02-21 /pmc/articles/PMC3931823/ /pubmed/24586944 http://dx.doi.org/10.1371/journal.pone.0089659 Text en © 2014 Di Martino et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Di Martino, Maria Teresa Gullà, Annamaria Gallo Cantafio, Maria Eugenia Altomare, Emanuela Amodio, Nicola Leone, Emanuela Morelli, Eugenio Lio, Santo Giovanni Caracciolo, Daniele Rossi, Marco Frandsen, Niels M. Tagliaferri, Pierosandro Tassone, Pierfrancesco In Vitro and In Vivo Activity of a Novel Locked Nucleic Acid (LNA)-Inhibitor-miR-221 against Multiple Myeloma Cells |
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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931823/ https://www.ncbi.nlm.nih.gov/pubmed/24586944 http://dx.doi.org/10.1371/journal.pone.0089659 |
work_keys_str_mv | AT dimartinomariateresa invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT gullaannamaria invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT gallocantafiomariaeugenia invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT altomareemanuela invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT amodionicola invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT leoneemanuela invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT morellieugenio invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT liosantogiovanni invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT caracciolodaniele invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT rossimarco invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT frandsennielsm invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT tagliaferripierosandro invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells AT tassonepierfrancesco invitroandinvivoactivityofanovellockednucleicacidlnainhibitormir221againstmultiplemyelomacells |