title: Inhibition of endopeptidase and exopeptidase activity of cathepsin B impairs extracellular matrix degradation and tumour invasion.
abstract: 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 μM) reduced extracellular degradation of collagen IV by MCF-10A neoT cells by 45-70% as determined by spectrofluorimetry and they (50 μM) attenuated intracellular collagen IV degradation by 40-60% as measured with flow cytometry. Furthermore, all three compounds (5 μM) impaired MCF-10A neoT cell invasion by 40-80% as assessed by measuring electrical impedance in real time. Compounds 1 and 3 (5 μM), 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Mitrović
authors.forename: Bojana
authors.initials: B
authors.lastname: Mirković
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Janko
authors.initials: J
authors.lastname: Kos
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D015394:Molecular Structure; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009600:Nitroquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000611681:2-(((8-hydroxy-5-nitroquinoline-7-yl)methyl)amino)acetonitrile; C000611683:7-((4-methylpiperidin-1yl)methyl)-5-nitroquinolin-8-ol; C000611682:8-(4-methylpiperidin-1-yl)-5-nitroquinoline; D009600:Nitroquinolines; D010880:Piperidines; D011480:Protease Inhibitors; D000607:Aminoacetonitrile; C533912:CTSB protein, human; D002401:Cathepsin B