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Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapyMitrović, Ana ...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.Source: Cellular and molecular life sciences. - ISSN 1420-682X (Vol. 79, no. 1, 2022, 14 str.)Type of material - article, component part ; adult, seriousPublish date - 2022Language - englishCOBISS.SI-ID - 92443651
Author | Mitrović, Ana ... |
Title | Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy |
Publication date | 2022-01-06 |
COBISS.SI-ID | 92443651 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
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Preprečevanje rezistence tumorskih celic na antiproteazno terapijo z inhibitorji katepsina X. | J4-8227-2017 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Farmacevtska biotehnologija: znanost za zdravje | P4-0127-2019 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Uporaba inhibitorjev katepsinov B in X za izboljšanje protitumorne terapije | Z3-9273-2018 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Proteoliza in njena regulacija | P1-0140-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
Files that belong to the publication
Link |
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https://link.springer.com/article/10.1007/s00018-021-04117-w |
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=142031 |
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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DRS, in which the journal is indexed
Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Mitrović, Ana | 36440 |
Završnik, Janja | 34458 |
Mikhaylov, Georgy | 37797 |
Knez, Damijan, farmacevt | 36438 |
Pečar Fonović, Urša | 19170 |
Matjan-Štefin, Petra | 53032 |
Butinar, Miha | 33315 |
Gobec, Stanislav, 1970- | 15284 |
Turk, Boris, 1964- | 07561 |
Kos, Janko, 1959- | 04648 |
Source: Personal bibliographies
and: SICRIS
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