Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model.

Biological Chemistry
U SchurigtT Reinheckel

Abstract

Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection of JPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, whi...Continue Reading

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Citations

May 14, 2009·Journal of Mammary Gland Biology and Neoplasia·Christine J Watson, Peter A Kreuzaler
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lisa SevenichThomas Reinheckel
Dec 14, 2011·Genes & Development·Tanaya ShreeJohanna A Joyce
Jan 24, 2012·Cancer Research·Nimali P WithanaBelinda S Parker
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Mar 4, 2021·Journal of Medicinal Chemistry·Rao SongTao Yang
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Mar 28, 2020·Biochemistry·Zhefu DaiYong Zhang

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