Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer

Int J Mol Sci. 2018 May 20;19(5):1524. doi: 10.3390/ijms19051524.


Wnt/β-catenin signaling is upregulated in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes and normal tissues. Current Wnt/β-catenin inhibitors, such as niclosamide, target the pathway nonspecifically and exhibit poor pharmacokinetics/pharmacodynamics in vivo. Niclosamide targets other pathways, including mTOR, STAT3 and Notch. Novel benzimidazoles have been developed to inhibit Wnt/β-catenin signaling with greater specificity. The compounds SRI33576 and SRI35889 were discovered to produce more cytotoxicity in TNBC cell lines than in noncancerous cells. The agents also downregulated Wnt/β-catenin signaling mediators LRP6, cyclin D1, survivin and nuclear active β-catenin. In addition, SRI33576 did not affect mTOR, STAT3 and Notch signaling in TNBC and noncancerous cells. SRI35889 inhibited mTOR signaling less in noncancerous than in cancerous cells, while not affecting STAT3 and Notch pathways. Compounds SRI32529, SRI35357 and SRI35361 were not selectively cytotoxic against TNBC cell lines compared to MCF10A cells. While SRI32529 inhibited Wnt/β-catenin signaling, the compound also mitigated mTOR, STAT3 and Notch signaling. SRI33576 and SRI35889 were identified as cytotoxic and selective inhibitors of Wnt/β-catenin signaling with therapeutic potential to treat TNBC in vivo.

Keywords: LRP6; Wnt/β-catenin signaling; benzimidazoles; receptor-targeted therapy; triple-negative breast cancer.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Triple Negative Breast Neoplasms / metabolism*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Antineoplastic Agents
  • Benzimidazoles
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Receptors, Notch
  • STAT3 Transcription Factor
  • Wnt Proteins
  • beta Catenin
  • TOR Serine-Threonine Kinases