Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA

Tumor-associated cell-free DNAs (cfDNA) play an important role in the promotion of metastases. Previous studies proved the high antimetastatic potential of bovine pancreatic DNase I and identified short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs)and fragments...

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Autores principales:	Ludmila Alekseeva, Aleksandra Sen’kova, Innokenty Savin, Marina Zenkova, Nadezhda Mironova
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DNase I Pulmozyme<sup>®</sup> drug repurposing circulating cell-free DNA neutrophil extracellular traps SINE elements Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/4cff534030294ce59b65306735044e74
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spelling	oai:doaj.org-article:4cff534030294ce59b65306735044e742021-11-11T17:28:28ZHuman Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA10.3390/ijms2221120741422-00671661-6596https://doaj.org/article/4cff534030294ce59b65306735044e742021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12074https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Tumor-associated cell-free DNAs (cfDNA) play an important role in the promotion of metastases. Previous studies proved the high antimetastatic potential of bovine pancreatic DNase I and identified short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs)and fragments of oncogenes in cfDNA as the main molecular targets of enzyme in the bloodstream. Here, recombinant human DNase I (commercial name Pulmozyme<sup>®</sup>), which is used for the treatment of cystic fibrosis in humans, was repurposed for the inhibition of lung metastases in the B16 melanoma model in mice. We found that Pulmozyme<sup>®</sup> strongly reduced migration and induced apoptosis of B16 cells <i>in vitro</i> and effectively inhibited metastases in lungs and liver <i>in vivo</i>. Pulmozyme<sup>®</sup> was shown to be two times more effective when administered intranasally (i.n.) than bovine DNase I, but intramuscular (i.m.) administration forced it to exhibit as high an antimetastatic activity as bovine DNase I. Both DNases administered to mice either i.m. or i.n. enhanced the DNase activity of blood serum to the level of healthy animals, significantly decreased cfDNA concentrations, efficiently degraded SINE and LINE repeats and c-Myc fragments in the bloodstream and induced apoptosis and disintegration of neutrophil extracellular traps in metastatic foci; as a result, this manifested as the inhibition of metastases spread. Thus, Pulmozyme<sup>®</sup>, which is already an approved drug, can be recommended for use in the treatment of lung metastases.Ludmila AlekseevaAleksandra Sen’kovaInnokenty SavinMarina ZenkovaNadezhda MironovaMDPI AGarticleDNase IPulmozyme<sup>®</sup>drug repurposingcirculating cell-free DNAneutrophil extracellular trapsSINE elementsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12074, p 12074 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNase I Pulmozyme<sup>®</sup> drug repurposing circulating cell-free DNA neutrophil extracellular traps SINE elements Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	DNase I Pulmozyme<sup>®</sup> drug repurposing circulating cell-free DNA neutrophil extracellular traps SINE elements Biology (General) QH301-705.5 Chemistry QD1-999 Ludmila Alekseeva Aleksandra Sen’kova Innokenty Savin Marina Zenkova Nadezhda Mironova Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA
description	Tumor-associated cell-free DNAs (cfDNA) play an important role in the promotion of metastases. Previous studies proved the high antimetastatic potential of bovine pancreatic DNase I and identified short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs)and fragments of oncogenes in cfDNA as the main molecular targets of enzyme in the bloodstream. Here, recombinant human DNase I (commercial name Pulmozyme<sup>®</sup>), which is used for the treatment of cystic fibrosis in humans, was repurposed for the inhibition of lung metastases in the B16 melanoma model in mice. We found that Pulmozyme<sup>®</sup> strongly reduced migration and induced apoptosis of B16 cells <i>in vitro</i> and effectively inhibited metastases in lungs and liver <i>in vivo</i>. Pulmozyme<sup>®</sup> was shown to be two times more effective when administered intranasally (i.n.) than bovine DNase I, but intramuscular (i.m.) administration forced it to exhibit as high an antimetastatic activity as bovine DNase I. Both DNases administered to mice either i.m. or i.n. enhanced the DNase activity of blood serum to the level of healthy animals, significantly decreased cfDNA concentrations, efficiently degraded SINE and LINE repeats and c-Myc fragments in the bloodstream and induced apoptosis and disintegration of neutrophil extracellular traps in metastatic foci; as a result, this manifested as the inhibition of metastases spread. Thus, Pulmozyme<sup>®</sup>, which is already an approved drug, can be recommended for use in the treatment of lung metastases.
format	article
author	Ludmila Alekseeva Aleksandra Sen’kova Innokenty Savin Marina Zenkova Nadezhda Mironova
author_facet	Ludmila Alekseeva Aleksandra Sen’kova Innokenty Savin Marina Zenkova Nadezhda Mironova
author_sort	Ludmila Alekseeva
title	Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA
title_short	Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA
title_full	Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA
title_fullStr	Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA
title_full_unstemmed	Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA
title_sort	human recombinant dnase i (pulmozyme<sup>®</sup>) inhibits lung metastases in murine metastatic b16 melanoma model that correlates with restoration of the dnase activity and the decrease sine/line and c-myc fragments in blood cell-free dna
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4cff534030294ce59b65306735044e74
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Human Recombinant DNase I (Pulmozyme<sup>®</sup>) Inhibits Lung Metastases in Murine Metastatic B16 Melanoma Model That Correlates with Restoration of the DNase Activity and the Decrease SINE/LINE and c-Myc Fragments in Blood Cell-Free DNA

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