Abstract
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.
Highlights
The antitumor and antimetastatic activity of bovine pancreatic deoxyribonuclease I (DNase I) was well investigated by our group
We should underline that it is the enzymatic activity of DNase I that determines its antitumor and antimetastatic effects
Pulmozyme® is a powerful tool for the inhibition of lung metastases, and its antimetastatic activity correlated with the restoration of DNase activity, a decrease in cell-free DNAs (cfDNA) concentrations and the specific degradation of the Myc oncogene and short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs) elements
Summary
Drug repurposing refers to a general approach in which a drug approved for the treatment of certain pathological states is tested against other diseases [1]. This approach is critical as it takes advantage of drugs with well-known pharmacokinetics, pharmacodynamics, toxicity profiles and even predictable dosages, as well as other investigated factors, such as side effects and the possibility of combination with other drugs. The growing attention to this strategy is strongly dependent on the ability to obtain accurate mechanistic views of the repurposed drug. It is on the basis of this information that the selected medication can be changed for a new indication.
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