Research Papers:

Addition of 2-(ethylamino)acetonitrile group to nitroxoline results in significantly improved anti-tumor activity in vitro and in vivo

Ana Mitrović, Izidor Sosič, Špela Kos, Urša Lampreht Tratar, Barbara Breznik, Simona Kranjc, Bojana Mirković, Stanislav Gobec, Tamara Lah, Maja Čemažar, Gregor Serša and Janko Kos _

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Oncotarget. 2017; 8:59136-59147. https://doi.org/10.18632/oncotarget.19296

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Ana Mitrović1, Izidor Sosič1, Špela Kos2, Urša Lampreht Tratar2, Barbara Breznik3,4, Simona Kranjc2, Bojana Mirković1, Stanislav Gobec1, Tamara Lah3, Maja Čemažar2, Gregor Serša2 and Janko Kos1,5

1Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia

2Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia

3Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia

4International Postgraduate School Jožef Stefan, 1000 Ljubljana, Slovenia

5Department of Biotechnology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia

Correspondence to:

Janko Kos, email: [email protected]

Keywords: nitroxoline derivative, cathepsin B, inhibition, tumor invasion, cell migration

Received: April 03, 2017    Accepted: June 10, 2017    Published: July 17, 2017


Lysosomal cysteine peptidase cathepsin B, involved in multiple processes associated with tumor progression, is validated as a target for anti-cancer therapy. Nitroxoline, a known antimicrobial agent, is a potent and selective inhibitor of cathepsin B, hence reducing tumor progression in vitro and in vivo. In order to further improve its anti-cancer properties we developed a number of derivatives using structure-based chemical synthesis. Of these, the 7-aminomethylated derivative (compound 17) exhibited significantly improved kinetic properties over nitroxoline, inhibiting cathepsin B endopeptidase activity selectively. In the present study, we have evaluated its anti-cancer properties. It was more effective than nitroxoline in reducing tumor cell invasion and migration, as determined in vitro on two-dimensional cell models and tumor spheroids, under either endpoint or real time conditions. Moreover, it exhibited improved action over nitroxoline in impairing tumor growth in vivo in LPB mouse fibrosarcoma tumors in C57Bl/6 mice. Taken together, the addition of a 2-(ethylamino)acetonitrile group to nitroxoline at position 7 significantly improves its pharmacological characteristics and its potential for use as an anti-cancer drug.

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