PUBLICATION
Suramin, a drug for the treatment of trypanosomiasis, reduces the prothrombotic and metastatic phenotypes of colorectal cancer cells by inhibiting hepsin
- Authors
- Zaragoza-Huesca, D., Rodenas, M.C., Peñas-Martínez, J., Pardo-Sánchez, I., Peña-García, J., Espín, S., Ricote, G., Nieto, A., García-Molina, F., Vicente, V., Lozano, M.L., Carmona-Bayonas, A., Mulero, V., Pérez-Sánchez, H., Martínez-Martínez, I.
- ID
- ZDB-PUB-231103-4
- Date
- 2023
- Source
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 168: 115814115814 (Journal)
- Registered Authors
- Mulero, Victor
- Keywords
- Cancer-associated thrombosis, Colorectal cancer, Hepsin, Suramin, Tumor invasion
- MeSH Terms
-
- Animals
- Caco-2 Cells
- Colorectal Neoplasms*/drug therapy
- Humans
- Molecular Docking Simulation
- Phenotype
- Suramin/pharmacology
- Suramin/therapeutic use
- Thrombin
- Trypanosomiasis*
- Zebrafish
- PubMed
- 37918256 Full text @ Biomed. Pharmacother.
Citation
Zaragoza-Huesca, D., Rodenas, M.C., Peñas-Martínez, J., Pardo-Sánchez, I., Peña-García, J., Espín, S., Ricote, G., Nieto, A., García-Molina, F., Vicente, V., Lozano, M.L., Carmona-Bayonas, A., Mulero, V., Pérez-Sánchez, H., Martínez-Martínez, I. (2023) Suramin, a drug for the treatment of trypanosomiasis, reduces the prothrombotic and metastatic phenotypes of colorectal cancer cells by inhibiting hepsin. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 168:115814115814.
Abstract
Recently, our group identified serine-protease hepsin from primary tumor as a biomarker of metastasis and thrombosis in patients with localized colorectal cancer. We described hepsin promotes invasion and thrombin generation of colorectal cancer cells in vitro and in vivo and identified venetoclax as a hepsin inhibitor that suppresses these effects. Now, we aspire to identify additional hepsin inhibitors, aiming to broaden the therapeutic choices for targeted intervention in colorectal cancer.
Methods We developed a virtual screening based on molecular docking between the hepsin active site and 2000 compounds from DrugBank. The most promising drug was validated in a hepsin activity assay. Subsequently, we measured the hepsin inhibitor effect on colorectal cancer cells with basal or overexpression of hepsin via wound-healing, gelatin matrix invasion, and plasma thrombin generation assays. Finally, a zebrafish model determined whether hepsin inhibition reduced the invasion of colorectal cancer cells overexpressing hepsin.
Results Suramin was the most potent hepsin inhibitor (docking score: -11.9691 Kcal/mol), with an IC50 of 0.66 µM. In Caco-2 cells with basal or overexpression of hepsin, suramin decreased migration and significantly reduced invasion and thrombin generation. Suramin did not reduce the thrombotic phenotype in the hepsin-negative colorectal cancer cells HCT-116 and DLD-1. Finally, suramin significantly reduced the in vivo invasion of Caco-2 cells overexpressing hepsin.
Conclusion Suramin is a novel hepsin inhibitor that reduces its protumorigenic and prothrombotic effects in colorectal cancer cells. This suggests the possibility of repurposing suramin and its derivatives to augment the repertoire of molecular targeted therapies against colorectal cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping