2. Academic Validation
  3. New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells

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.
Begoña Alburquerque-González  # 1,  Manuel Bernabé-García  # 2,  Silvia Montoro-García 3,  Ángel Bernabé-García 4,  Priscila Campioni Rodrigues 5 6,  Javier Ruiz Sanz 7,  Fernando F López-Calderón 1,  Irene Luque 7,  Francisco José Nicolas 3,  María Luisa Cayuela 4,  Tuula Salo 5 6 8 9,  Horacio Pérez-Sánchez 10,  Pablo Conesa-Zamora 11 12 13
Affiliations

Affiliations

  • 1 Pathology and Histology Department, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, 30107, Guadalupe, Murcia, Spain.
  • 2 Research group "Telomerasa, Envejecimiento y Cáncer," CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.
  • 3 Cell Culture Lab, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain.
  • 4 Research group "Regeneración, oncología molecular y TGF-β", Institute for Biohealth Research from Murcia (IMIB), Hospital Clínico Universitario Virgen de la ArrixacaCarretera Madrid-Cartagena, El Palmar, Spain.
  • 5 Cancer Research and Translational Medicine Research Unit, University of Oulu, Aapistie 5A, FI-90220, Oulu, Finland.
  • 6 Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
  • 7 Department of Physical Chemistry and Institute of Biotechnology, University of Granada, Campus Fuentenueva s/n, 18071, Granada, Spain.
  • 8 Institute of Oral and Maxillofacial Disease, University of Helsinki, Helsinki, Finland.
  • 9 HUSLAB, Department of Pathology, Helsinki University Hospital, Helsinki, Finland.
  • 10 Structural Bioinformatics and High Performance Computing (BIO-HPC) Research Group, Universidad Católica de Murcia (UCAM), Guadalupe, Spain. hperez@ucam.edu.
  • 11 Pathology and Histology Department, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, 30107, Guadalupe, Murcia, Spain. pablo.conesa@carm.es.
  • 12 Clinical Analysis Department, Group of Molecular Pathology and Pharmacogenetics, Institute for Biohealth Research from Murcia (IMIB), Hospital Universitario Santa Lucía, c/Mezquita sn, 30202, Cartagena, Spain. pablo.conesa@carm.es.
  • 13 C/Mezquita s/n CP, 30202, Cartagena, Murcia, Spain. pablo.conesa@carm.es.
  • # Contributed equally.
PMID: 32080340 DOI: 10.1038/s12276-020-0389-x
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.

Figures
Products