New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells Alburquerque González, Begoña Bernabe Garcia, Manuel Montoro Garcia, Silvia Bernabe Garcia, Angel Campioni Rodrigues, Priscila Ruiz Sanz, Javier López Calderón, Fernando Luque Fernández, Irene Nicolás, Francisco José Cayuela Fuentes, Maria Luisa Salo, Tuula Perez Sanchez, Horacio Conesa Zamora, Pablo Imipramine Fascin1 inhibitor Colorectal cancer Antitumoral rol Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors. 2025-01-21T10:32:07Z 2025-01-21T10:32:07Z 2020-02 journal article Alburquerque-González B, Bernabé-García M, Montoro-García S, Bernabé-García Á, Rodrigues PC, Ruiz Sanz J, López-Calderón FF, Luque I, Nicolas FJ, Cayuela ML, Salo T, Pérez-Sánchez H, Conesa-Zamora P. New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells. Exp Mol Med. 2020 Feb;52(2):281-292. doi: 10.1038/s12276-020-0389-x. Epub 2020 Feb 20. PMID: 32080340; PMCID: PMC7062870. https://hdl.handle.net/10481/99821 https://doi.org/10.1038/s12276-020-0389-x eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Editor Nature Publishing Group UK