Abstract
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.
Highlights
Of all cancers, breast cancer affects women the most with an incidence of about 12%
Breast cancer affects women the most with an incidence of about 12%. High morbidity of this disease is associated with triple-negative breast cancer (TNBC), which accounts for 10–20% of all breast cancers [1,2,3] The moniker of the disease derives from lack of progesterone, estrogen and HER2 receptors, commonly targeted by chemotherapy, hormone therapy and HER2 antibody
IC50 values for TNBC cell lines treated with niclosamide, an inhibitor of multiple signaling pathways, ranged from 0.3 to 1.0 μM, while the IC50 value for MCF10A cells was 1.0 μM
Summary
Breast cancer affects women the most with an incidence of about 12% High morbidity of this disease is associated with triple-negative breast cancer (TNBC), which accounts for 10–20% of all breast cancers [1,2,3] The moniker of the disease derives from lack of progesterone, estrogen and HER2 receptors, commonly targeted by chemotherapy, hormone therapy and HER2 antibody. As a result, these cancers exhibit drug resistance [4]. Lack of phosphorylation enables β-catenin to avoid ubiquitination and degradation, allowing the protein to translocate to the nucleus, bind to TCF/LEF transcription factors and promote transcription of target genes, such as cyclin D1 and survivin, that drive tumorigenesis and cell proliferation [9,10,11,12]
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