Cargando…
Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer
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. Niclosamid...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983770/ https://www.ncbi.nlm.nih.gov/pubmed/29783777 http://dx.doi.org/10.3390/ijms19051524 |
_version_ | 1783328495611412480 |
---|---|
author | Gangrade, Abhishek Pathak, Vibha Augelli-Szafran, Corinne E. Wei, Han-Xun Oliver, Patsy Suto, Mark Buchsbaum, Donald J. |
author_facet | Gangrade, Abhishek Pathak, Vibha Augelli-Szafran, Corinne E. Wei, Han-Xun Oliver, Patsy Suto, Mark Buchsbaum, Donald J. |
author_sort | Gangrade, Abhishek |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5983770 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-59837702018-06-05 Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer Gangrade, Abhishek Pathak, Vibha Augelli-Szafran, Corinne E. Wei, Han-Xun Oliver, Patsy Suto, Mark Buchsbaum, Donald J. Int J Mol Sci Article 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. MDPI 2018-05-20 /pmc/articles/PMC5983770/ /pubmed/29783777 http://dx.doi.org/10.3390/ijms19051524 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gangrade, Abhishek Pathak, Vibha Augelli-Szafran, Corinne E. Wei, Han-Xun Oliver, Patsy Suto, Mark Buchsbaum, Donald J. Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer |
title | Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer |
title_full | Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer |
title_fullStr | Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer |
title_full_unstemmed | Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer |
title_short | Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer |
title_sort | preferential inhibition of wnt/β-catenin signaling by novel benzimidazole compounds in triple-negative breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983770/ https://www.ncbi.nlm.nih.gov/pubmed/29783777 http://dx.doi.org/10.3390/ijms19051524 |
work_keys_str_mv | AT gangradeabhishek preferentialinhibitionofwntbcateninsignalingbynovelbenzimidazolecompoundsintriplenegativebreastcancer AT pathakvibha preferentialinhibitionofwntbcateninsignalingbynovelbenzimidazolecompoundsintriplenegativebreastcancer AT augelliszafrancorinnee preferentialinhibitionofwntbcateninsignalingbynovelbenzimidazolecompoundsintriplenegativebreastcancer AT weihanxun preferentialinhibitionofwntbcateninsignalingbynovelbenzimidazolecompoundsintriplenegativebreastcancer AT oliverpatsy preferentialinhibitionofwntbcateninsignalingbynovelbenzimidazolecompoundsintriplenegativebreastcancer AT sutomark preferentialinhibitionofwntbcateninsignalingbynovelbenzimidazolecompoundsintriplenegativebreastcancer AT buchsbaumdonaldj preferentialinhibitionofwntbcateninsignalingbynovelbenzimidazolecompoundsintriplenegativebreastcancer |