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Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy
ID Mitrović, Ana (Author), ID Završnik, Janja (Author), ID Mikhaylov, Georgy (Author), ID Knez, Damijan (Author), ID Pečar Fonović, Urša (Author), ID Matjan-Štefin, Petra (Author), ID Butinar, Miha (Author), ID Gobec, Stanislav (Author), ID Turk, Boris (Author), ID Kos, Janko (Author)

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Abstract
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 This link opens in a new window
UDC:577
ISSN on article:1420-682X
DOI:10.1007/s00018-021-04117-w This link opens in a new window
COBISS.SI-ID:92443651 This link opens in a new window
Publication date in RUL:17.10.2022
Views:519
Downloads:74
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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 This link opens in a new window

Licences

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.

Projects

Funder:ARRS - Slovenian Research Agency
Project number:J4-8227-2017
Name:Preprečevanje rezistence tumorskih celic na antiproteazno terapijo z inhibitorji katepsina X.

Funder:ARRS - Slovenian Research Agency
Project number:P4-0127-2019
Name:Farmacevtska biotehnologija: znanost za zdravje

Funder:ARRS - Slovenian Research Agency
Project number:Z3-9273-2018
Name:Uporaba inhibitorjev katepsinov B in X za izboljšanje protitumorne terapije

Funder:ARRS - Slovenian Research Agency
Project number:P1-0140-2015
Name:Proteoliza in njena regulacija

Funder:ARRS - Slovenian Research Agency
Project number:P1-0208-2015
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

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