Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy

Mitrović, Ana (author), Završnik, Janja (author), Mikhaylov, Georgy (author), Knez, Damijan (author), Pečar Fonović, Urša (author), Matjan-Štefin, Petra (author), Butinar, Miha (author), Gobec, Stanislav (author), Turk, Boris (author), Kos, Janko (author)

New therapeutic targets that could improve current antitumor therapy and overcome cancer resistance are urgently needed. Promising candidates are lysosomal cysteine cathepsins, proteolytical enzymes involved in various critical steps during cancer progression. Among them, cathepsin X, which acts solely as a carboxypeptidase, has received much attention. Our results indicate that the triazole-based selective reversible inhibitor of cathepsin X named Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) significantly reduces tumor progression, both in vitro in cell-based functional assays and in vivo in two independent tumor mouse models: the FVB/PyMT transgenic and MMTV-PyMT orthotopic breast cancer mouse models. One of the mechanisms by which cathepsin X contributes to cancer progression is the compensation of cathepsin-B activity loss. Our results confirm that cathepsin-B inhibition is compensated by an increase in cathepsin X activity and protein levels. Furthermore, the simultaneous inhibition of both cathepsins B and X with potent, selective, reversible inhibitors exerted a synergistic effect in impairing processes of tumor progression in in vitro cell-based assays of tumor cell migration and spheroid growth. Taken together, our data demonstrate that Z9 impairs tumor progression both in vitro and in vivo and can be used in combination with other peptidase inhibitors as an innovative approach to overcome resistance to antipeptidase therapy.

• Language: English
• Keywords: cathepsin X, cathepsin B, inhibitors, cancer, antitumor therapy, invasion
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: Str. 34-1-34-14
• Numbering: Vol. 79, no. 1
• PID: 20.500.12556/RUL-142031
• UDC: 577
• ISSN on article: 1420-682X
• DOI: 10.1007/s00018-021-04117-w
• COBISS.SI-ID: 92443651
• Publication date in RUL: 17.10.2022

Record is a part of a journal

• Title: Cellular and molecular life sciences
• Shortened title: Cell Mol Life Sci
• Publisher: Birkhäuser
• ISSN: 1420-682X
• COBISS.SI-ID: 1615380

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• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.