4.7 Article

Human Recombinant DNase I (Pulmozyme) 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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出版社

MDPI
DOI: 10.3390/ijms222112074

关键词

DNase I; Pulmozyme; drug repurposing; circulating cell-free DNA; neutrophil extracellular traps; SINE elements; LINE elements; tumor; metastasis

资金

  1. Russian Science Foundation [19-74-30011]
  2. Russian Government [121031300044-5]
  3. Russian Science Foundation [19-74-30011] Funding Source: Russian Science Foundation

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The study showed that recombinant human DNase I Pulmozyme effectively inhibited lung metastases in the B16 melanoma model in mice, demonstrating strong antimetastatic activity both in vitro and in vivo. Additionally, Pulmozyme administration enhanced blood serum DNase activity, decreased cfDNA concentrations, efficiently degraded SINE and LINE repeats, and induced apoptosis in metastatic foci.
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), 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 strongly reduced migration and induced apoptosis of B16 cells in vitro and effectively inhibited metastases in lungs and liver in vivo. Pulmozyme 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, which is already an approved drug, can be recommended for use in the treatment of lung metastases.

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