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Updated: May 21, 2026
A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
A high throughput screen identifies Nefopam as targeting cell proliferation in β-catenin driven neoplastic and
Raymond Poon1, Helen Hong, Xin Wei
1Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Abstract:
Fibroproliferative disorders include neoplastic and reactive processes (e.g. desmoid tumor and hypertrophic scars). They are characterized by activation of β-catenin signaling, and effective pharmacologic approaches are lacking. Here we undertook a high throughput screen using human desmoid tumor cell cultures to identify agents that would inhibit cell viability in tumor cells but not normal fibroblasts. Agents were then tested in additional cell cultures for an effect on cell proliferation, apoptosis, and β-catenin protein level. Ultimately they were tested in Apc1638N mice, which develop desmoid tumors, as well as in wild type mice subjected to full thickness skin wounds. The screen identified Neofopam, as an agent that inhibited cell numbers to 42% of baseline in cell cultures from β-catenin driven fibroproliferative disorders. Nefopam decreased cell proliferation and β-catenin protein level to 50% of baseline in these same cell cultures. The half maximal effective concentration in-vitro was 0.5 uM and there was a plateau in the effect after 48 hours of treatment. Nefopam caused a 45% decline in tumor number, 33% decline in tumor volume, and a 40% decline in scar size when tested in mice. There was also a 50% decline in β-catenin level in-vivo. Nefopam targets β-catenin protein level in mesenchymal cells in-vitro and in-vivo, and may be an effective therapy for neoplastic and reactive processes driven by β-catenin mediated signaling.
Insights
Nefopam effectively targets beta-catenin signaling in fibroproliferative disorders, reducing tumor cell viability and growth. This agent shows promise for treating conditions like desmoid tumors and hypertrophic scars.
Area of Science:
- Pharmacology and Molecular Biology
- Oncology
- Dermatology
Background:
- Fibroproliferative disorders, including desmoid tumors and hypertrophic scars, are driven by aberrant beta-catenin signaling.
- Current pharmacologic treatments for these conditions remain limited.
- Identifying novel therapeutic agents targeting beta-catenin is crucial.
Purpose of the Study:
- To identify agents inhibiting cell viability in beta-catenin-driven fibroproliferative disorders.
- To evaluate the efficacy of identified agents on cell proliferation, apoptosis, and beta-catenin levels.
- To assess the therapeutic potential of Nefopam in preclinical models.
Main Methods:
- High-throughput screening of human desmoid tumor cell cultures.
- In vitro testing for effects on cell proliferation, apoptosis, and beta-catenin protein.
- In vivo studies using Apc1638N mice with desmoid tumors and wild-type mice with skin wounds.
Main Results:
- Nefopam inhibited cell numbers by 42% in beta-catenin-driven fibroproliferative disorder cell cultures.
- Nefopam reduced cell proliferation and beta-catenin protein levels by 50% in vitro.
- In vivo, Nefopam decreased tumor number by 45%, tumor volume by 33%, and scar size by 40%, with a 50% decline in beta-catenin levels.
Conclusions:
- Nefopam effectively targets beta-catenin protein levels in mesenchymal cells both in vitro and in vivo.
- Nefopam demonstrates significant therapeutic potential for neoplastic and reactive fibroproliferative disorders mediated by beta-catenin signaling.
- Further investigation into Nefopam as a treatment for these conditions is warranted.
