New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells
Identificadores
URI: https://hdl.handle.net/10481/99821Metadatos
Mostrar el registro completo del ítemAutor
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, PabloEditorial
Editor Nature Publishing Group UK
Materia
Imipramine Fascin1 inhibitor Colorectal cancer Antitumoral rol
Fecha
2020-02Referencia bibliográfica
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.
Patrocinador
This work is supported by the Instituto de Salud Carlos III (Spanish Ministry of Health) and FEDER funds (ref: PI15/00626). B.A.-G. belongs to the “Programa de Doctorado en ciencias de la Salud” from the Catholic University of Murcia (UCAM) and holds a predoctoral grant from UCAM. S.M.-G. was supported by the Fundación Séneca and PCR by the Finnish Cultural and Sigrid Juselius Foundations (2017–2018 and 2018–2019 grants).Resumen
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.