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New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells

Experimental & Molecular Medicine 2020년 52권 2호 p.7 ~ 7
 ( Alburquerque-Gonzalez Begona ) - Universidad Catolica San Antonio de Murcia Facultad de Ciencias de la Salud Pathology and Histology Department

 ( Bernabe-Garcia Manuel ) - Hospital Clinico Universitario Virgen de la Arrixaca
 ( Montoro-Garcia Silvia ) - Universidad Catolica San Antonio de Murcia Facultad de Ciencias de la Salud
 ( Bernabe-Garcia Angel ) - Hospital Clinico Universitario Virgen de la Arrixaca Carretera Madrid-Cartagena
 ( Rodrigues Priscila Campioni ) - University of Oulu Cancer Research and Translational Medicine Research Unit
 ( Sanz Javier Ruiz ) - University of Granada Department of Physical Chemistry
 ( Lopez-Calderon Fernando F. ) - Universidad Catolica San Antonio de Murcia Facultad de Ciencias de la Salud Pathology and Histology Department
 ( Luque Irene ) - University of Granada Department of Physical Chemistry
 ( Nicolas Francisco Jose ) - Universidad Catolica San Antonio de Murcia Facultad de Ciencias de la Salud
 ( Cayuela Maria Luisa ) - Hospital Clinico Universitario Virgen de la Arrixaca Carretera Madrid-Cartagena
 ( Salo Tuula ) - University of Oulu Cancer Research and Translational Medicine Research Unit
 ( Perez-Sanchez Horacio ) - Universidad Catolica de Murcia Structural Bioinformatics and High Performance Computing Research Group
 ( Conesa-Zamora Pablo ) - Universidad Catolica San Antonio de Murcia Facultad de Ciencias de la Salud Pathology and Histology Department

Abstract


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.

키워드

Colon cancer; Drug development; Lamellipodia
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