Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 1, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-04117-w
Keywords
Cathepsin X; Cathepsin B; Inhibitors; Cancer; Antitumor therapy; Invasion
Categories
Funding
- Slovenian Research Agency [J4-8227, P4-0127, Z3-9273, P1-0140, P1-0208]
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The study highlights the potential of a triazole-based selective reversible inhibitor, Z9, in reducing tumor progression by targeting lysosomal cysteine cathepsin, particularly cathepsin X. The simultaneous inhibition of cathepsin X and cathepsin B shows a synergistic effect in impairing tumor cell migration and growth. This research reveals the innovative approach of using Z9 in combination with other peptidase inhibitors to overcome resistance to antipeptidase therapy.
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.
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