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Cathepsin B is a lysosomal cysteine protease that is implicated in a number of physiological processes, including protein turnover in lysosomes. Changes in its expression are associated with a variety of pathological processes, including cancer. Due to the structural feature, termed the occluding loop, cathepsin B differs from other cysteine proteases in possessing both, endopeptidase and exopeptidase activity. Here we investigated the impact of both cathepsin B activities on intracellular and extracellular collagen IV degradation and tumour cell invasion using new selective synthetic inhibitors, 2-{[(8-hydroxy-5-nitroquinoline-7-yl)methyl]amino}-acetonitrile ( 1 ), 8-(4-methylpiperidin-1-yl)-5-nitroquinoline ( 2 ) and 7-[(4-methylpiperidin-1yl)methyl]-5-nitroquinolin-8-ol ( 3 ). All three compounds (5 μ m ) reduced extracellular degradation of collagen IV by MCF-10A neoT cells by 45–70% as determined by spectrofluorimetry and they (50 μ m ) attenuated intracellular collagen IV degradation by 40-60% as measured with flow cytometry. Furthermore, all three compounds (5 μ m ) impaired MCF-10A neoT cell invasion by 40–80% as assessed by measuring electrical impedance in real time. Compounds  1  and  3  (5 μ m ), but not compound  2 , significantly reduced the growth of MMTV-PyMT multicellular tumour spheroids. Collectively, these data suggest that the efficient strategy to impair harmful cathepsin B activity in tumour progression may include simultaneous and potent inhibition of cathepsin B endopeptidase and exopeptidase activities.

Inhibition of endopeptidase and exopeptidase activity of cathepsin B impairs extracellular matrix degradation and tumour invasion