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

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.

• Authors: Bojana Mirković, Boštjan Markelc, Miha Butinar, Ana Mitrović, Izidor Sosič, Stanislav Gobec, Olga Vasiljeva, Boris Turk, Maja Čemažar, Gregor Serša, Janko Kos
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 22 Pg. 19027-42 (Aug 07 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25848918 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Nitroquinolines
• nitroxoline
• Cathepsin B

Topics

• Angiogenesis Inducing Agents (pharmacology)
• Animals
• Case-Control Studies
• Cathepsin B (antagonists & inhibitors, metabolism)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Disease Progression
• Endothelial Cells (drug effects)
• Female
• Fibrosarcoma (blood supply, drug therapy, enzymology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasm Metastasis
• Nitroquinolines (pharmacology)
• Random Allocation
• Sarcoma, Experimental (blood supply, drug therapy, enzymology)
• Spheroids, Cellular