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A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their the...

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Autores principales: Cipolletti, Manuela, Bartoloni, Stefania, Busonero, Claudia, Parente, Martina, Leone, Stefano, Acconcia, Filippo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000495/
https://www.ncbi.nlm.nih.gov/pubmed/33805656
http://dx.doi.org/10.3390/ijms22062915
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author Cipolletti, Manuela
Bartoloni, Stefania
Busonero, Claudia
Parente, Martina
Leone, Stefano
Acconcia, Filippo
author_facet Cipolletti, Manuela
Bartoloni, Stefania
Busonero, Claudia
Parente, Martina
Leone, Stefano
Acconcia, Filippo
author_sort Cipolletti, Manuela
collection PubMed
description 17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.
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spelling pubmed-80004952021-03-28 A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells Cipolletti, Manuela Bartoloni, Stefania Busonero, Claudia Parente, Martina Leone, Stefano Acconcia, Filippo Int J Mol Sci Article 17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity. MDPI 2021-03-13 /pmc/articles/PMC8000495/ /pubmed/33805656 http://dx.doi.org/10.3390/ijms22062915 Text en © 2021 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
Cipolletti, Manuela
Bartoloni, Stefania
Busonero, Claudia
Parente, Martina
Leone, Stefano
Acconcia, Filippo
A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells
title A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells
title_full A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells
title_fullStr A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells
title_full_unstemmed A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells
title_short A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells
title_sort new anti-estrogen discovery platform identifies fda-approved imidazole anti-fungal drugs as bioactive compounds against erα expressing breast cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000495/
https://www.ncbi.nlm.nih.gov/pubmed/33805656
http://dx.doi.org/10.3390/ijms22062915
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