A high throughput screen identifies Nefopam as targeting cell proliferation in β-catenin driven neoplastic and reactive fibroproliferative disorders.
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.
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Raymond
R
Poon
Helen
H
Hong
Xin
X
Wei
James
J
Pan
Benjamin A
BA
Alman
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D018222:Desmoid Tumors / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D009340:Nefopam / Q000494:pharmacology* / Q000627:therapeutic use; D010641:Phenotype; D012867:Skin / Q000293:injuries; D014945:Wound Healing / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
D000970:Antineoplastic Agents; D051176:beta Catenin; D009340:Nefopam