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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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:59:38Z |
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| id | doaj.art-4cff534030294ce59b65306735044e74 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T05:59:38Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4cff534030294ce59b65306735044e742023-11-22T21:02:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122211207410.3390/ijms222112074Human 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 DNALudmila Alekseeva0Aleksandra Sen’kova1Innokenty Savin2Marina Zenkova3Nadezhda Mironova4Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, 630090 Novosibirsk, RussiaInstitute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev ave., 8, 630090 Novosibirsk, RussiaTumor-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.https://www.mdpi.com/1422-0067/22/21/12074DNase IPulmozyme<sup>®</sup>drug repurposingcirculating cell-free DNAneutrophil extracellular trapsSINE elements |
| spellingShingle | 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 International Journal of Molecular Sciences DNase I Pulmozyme<sup>®</sup> drug repurposing circulating cell-free DNA neutrophil extracellular traps SINE elements |
| 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_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_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_sort | human recombinant dnase i pulmozyme sup r 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 |
| topic | DNase I Pulmozyme<sup>®</sup> drug repurposing circulating cell-free DNA neutrophil extracellular traps SINE elements |
| url | https://www.mdpi.com/1422-0067/22/21/12074 |
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