Oncotarget

Research Papers:

Nitroxoline impairs tumor progression in vitro and in vivo by regulating cathepsin B activity

Bojana Mirković _, Boštjan Markelc, Miha Butinar, Ana Mitrović, Izidor Sosič, Stanislav Gobec, Olga Vasiljeva, Boris Turk, Maja Čemažar, Gregor Serša & Janko Kos

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Oncotarget. 2015; 6:19027-19042. https://doi.org/10.18632/oncotarget.3699

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Abstract

Bojana Mirković1,*, Boštjan Markelc2,*, Miha Butinar3,*, Ana Mitrović1, Izidor Sosič1, Stanislav Gobec1, Olga Vasiljeva3, Boris Turk3,4,5, Maja Čemažar2, Gregor Serša2 and Janko Kos1,6

1 Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

2 Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia

3 Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia

4 Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Ljubljana, Slovenia

5 Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia

6 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia

* These authors have equally contributed to this work

Correspondence to:

Bojana Mirković, email:

Janko Kos, email:

Keywords: nitroxoline, cathepsin B, tumor invasion, angiogenesis, metastasis

Received: November 01, 2014 Accepted: March 05, 2015 Published: March 30, 2015

Abstract

Cathepsin B is a ubiquitously expressed lysosomal cysteine protease that participates in protein turnover within lysosomes. However, its protein and activity levels have been shown to be increased in cancer. Cathepsin B endopeptidase activity is involved in the degradation of extracellular matrix, a process that promotes tumor invasion, metastasis and angiogenesis. Previously, we reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin B. In the present study, we elucidated its anti-tumor properties in in vitro and in vivo tumor models.

Tumor and endothelial cell lines with high levels of active cathepsin B were selected for functional analysis of nitroxoline in vitro. Nitroxoline significantly reduced extracellular DQ-collagen IV degradation by all evaluated cancer cell lines using spectrofluorimetry. Nitroxoline also markedly decreased tumor cell invasion monitored in real time and reduced the invasive growth of multicellular tumor spheroids, used as a 3D in vitro model of tumor invasion. Additionally, endothelial tube formation was significantly reduced by nitroxoline in an in vitro angiogenesis assay. Finally, nitroxoline significantly abrogated tumor growth, angiogenesis and metastasis in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models. Overall, our results designate nitroxoline as a promising drug candidate for anti-cancer treatment.


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