A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions

Abstract

SUMMARYThe actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascinpathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.

Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment

“…However, some widely used TCAs, such as imipramine, desipramine, and amitriptyline, have emerged as possible promising repurposing drugs in colorectal cancer [116]. Following this line, in 2020, Alburquerque-Gonzalez et al showed that imipramine attenuated cell migration and invasion of colorectal cancer cells by inhibition of fascin [71], a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis [117]. This was the first study that demonstrated an antitumoral role of imipramine as a fascin inhibitor [118].…”