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

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.

How does fascin promote cancer metastasis?

“…Since fascin is not expressed in normal epithelium but highly overexpressed in metastatic cancer, it is considered to be a promising target to prevent metastasis. Several fascin inhibitors targeting fascin‐bundling activities have been developed [6,19,124–126]. These inhibitors have been used to inhibit cell migration/invasion in vitro and cancer metastasis in mouse models [6,19,125–127].…”

Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing

“…In 2006, Arimochi et al [ 58 , 59 ] have shown that, in human HT29 and HCT116 colon carcinoma cells, TCAs reduce cell viability in a concentration-dependent manner and cause apoptotic cell death through either a non-mitochondrial or a mitochondrial pathway. Recently, Begona et al [ 60 ] demonstrated the anti-invasive and antimetastatic properties of imipramine thanks to the anti-Fascin 1 activity in serrated colon adenocarcinoma cells.…”

Refocusing the Use of Psychiatric Drugs for Treatment of Gastrointestinal Cancers

“…Imipramine also compromises HCT116 cells viability at low concentrations and inhibits lamellipodium formation, cell migration and invasion by affecting fascin1 (33). On the other hand, has been reported that paroxetine reduces cell viability and increases apoptosis; it also inhibits colony and 3D spheroid formation in HCT116 and HT29 cell lines.…”