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

Dis Model Mech. 2013 Jan;6(1):217-35. doi: 10.1242/dmm.008243. Epub 2012 Aug 23.

Abstract

The 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 fascin-pathway 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents / pharmacology*
  • Biological Assay / methods
  • Brain / growth & development
  • Brain Neoplasms / drug therapy
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Cells, Cultured
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drug Discovery / methods
  • Drug Evaluation, Preclinical / methods*
  • Drug Screening Assays, Antitumor / methods
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Microfilament Proteins / antagonists & inhibitors*
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / genetics
  • Microfilament Proteins / physiology
  • Models, Neurological
  • Neoplasm Metastasis / prevention & control
  • Neuronal Plasticity / drug effects
  • Neurons / cytology
  • Neurons / drug effects
  • Nootropic Agents / pharmacology*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Microfilament Proteins
  • Nootropic Agents
  • fascin