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.