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...

Descripción completa

Detalles Bibliográficos
Autores principales: Gangrade, Abhishek, Pathak, Vibha, Augelli-Szafran, Corinne E., Wei, Han-Xun, Oliver, Patsy, Suto, Mark, Buchsbaum, Donald J.
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