ArticleMolecular cancer2016
A bioavailable cathepsin S nitrile inhibitor abrogates tumor development.
Article in Molecular cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 35 citations in OpenAlex.
- Structural Modifications of Covalent Cathepsin S Inhibitors: Impact on Affinity, Selectivity, and Permeability.ACS medicinal chemistry letters · 2024Article
- Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy.Frontiers in pharmacology · 2023Article
- Proteomics changes after negative pressure wound therapy in diabetic foot ulcers.Molecular medicine reports · 2021Article
- Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in AdultMediators of inflammation · 2021Article
- Procathepsin V Is Secreted in a TSH Regulated Manner from Human Thyroid Epithelial Cells and Is Accessible to an Activity-Based Probe.International journal of molecular sciences · 2020Article
- Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma.Blood · 2020Article
- Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery.Cells · 2020Review
- Expression of Proteolytic Enzymes by Small Cell Lung Cancer Circulating Tumor Cell Lines.Cancers · 2019Article
- A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer.Journal of oncology · 2019Article
- Microarray and proteome array in an atherosclerosis mouse model for identification of biomarkers in whole blood.International journal of medical sciences · 2019Article
- Inhibition of cathepsin S confers sensitivity to methyl protodioscin in oral cancer cells via activation of p38 MAPK/JNK signaling pathways.Scientific reports · 2017Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
backgroundCathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models.
methodsValidation of cathepsin S selectivity was carried out by assaying fluorogenic substrate turnover using recombinant cathepsin protease. Complete kinetic analysis was carried out and true K i values calculated. Abrogation of tumour invasion using murine MC38 and human MCF7 cell lines were carried out in vitro using a transwell migration assay. Effect on endothelial tube formation was evaluated using primary HUVEC cells. The effect of inhibitor in vivo on MC38 and MCF7 tumor progression was evaluated using cells propagated in C57BL/6 and BALB/c mice respectively. Subsequent immunohistochemical staining of proliferation (Ki67) and apoptosis (TUNEL) was carried out on MCF7 tumors.
resultsWe confirmed that this inhibitor was able to selectively target cathepsin S over family members K, V, L and B. The inhibitor also significantly reduced MC38 and MCF7 cell invasion and furthermore, significantly reduced HUVEC endothelial tubule formation in vitro. In vivo analysis revealed that the compound could significantly reduce tumor volume in murine MC38 syngeneic and MCF7 xenograft models. Immunohistochemical analysis of MCF7 tumors revealed cathepsin S inhibitor treatment significantly reduced proliferation and increased apoptosis.
conclusionsIn summary, these results highlight the characterisation of this nitrile cathepsin S inhibitor using in vitro and in vivo tumor models, presenting a compound which may be used to further dissect the role of cathepsin S in cancer progression and may hold therapeutic potential.
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