Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α
Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-α (ER-α) and toxic compounds, including the DDD derivatives. We used...
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MDPI AG
2021-06-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/6/681 |
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| author | Elisa Rossini Edoardo Giacopuzzi Fabrizio Gangemi Mariangela Tamburello Deborah Cosentini Andrea Abate Marta Laganà Alfredo Berruti Salvatore Grisanti Sandra Sigala |
| author_facet | Elisa Rossini Edoardo Giacopuzzi Fabrizio Gangemi Mariangela Tamburello Deborah Cosentini Andrea Abate Marta Laganà Alfredo Berruti Salvatore Grisanti Sandra Sigala |
| author_sort | Elisa Rossini |
| collection | DOAJ |
| description | Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-α (ER-α) and toxic compounds, including the DDD derivatives. We used molecular docking and molecular dynamics (MD) simulations to explore the possible interaction between mitotane and the ER-α receptor and the induced conformational changes. The ER-α expressing MCF-7 cells were exposed to mitotane with/without tamoxifen, and the cell viability/proliferation was evaluated by MTT assay and direct count. The transient ER-α silencing was performed using two ER-α siRNA (50 nM) and verified by Western blot. MDA-MB-231 cells were used as a negative control. Mitotane showed a similar docking configuration to 17β-estradiol and bisphenol A (BPA) and a significant binding affinity to ER-α. MD simulations showed that mitotane preserves the active conformation of ER-α more than both BPA and Bisphenol C, classifying it as an agonist. Exposure of MCF-7 cells to mitotane led to the concentration-dependent increase of cell viability and proliferation, which was reduced in the presence of tamoxifen and nullified by the transient ER-α knock-down. Integrating bioinformatics approaches with cell biology and pharmacological methods, we demonstrated that mitotane directly binds and activates ER-α. |
| first_indexed | 2024-03-10T10:21:17Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T10:21:17Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-3d65a0c8f56d4c0eb2ee03b3eecb0cdf2023-11-22T00:24:19ZengMDPI AGBiomedicines2227-90592021-06-019668110.3390/biomedicines9060681Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-αElisa Rossini0Edoardo Giacopuzzi1Fabrizio Gangemi2Mariangela Tamburello3Deborah Cosentini4Andrea Abate5Marta Laganà6Alfredo Berruti7Salvatore Grisanti8Sandra Sigala9Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyWellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UKUnit of Physics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySection of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyMedical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at A.S.S.T. Spedali Civili di Brescia, 25123 Brescia, ItalySection of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyMedical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at A.S.S.T. Spedali Civili di Brescia, 25123 Brescia, ItalyMedical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at A.S.S.T. Spedali Civili di Brescia, 25123 Brescia, ItalyMedical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at A.S.S.T. Spedali Civili di Brescia, 25123 Brescia, ItalySection of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyMitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-α (ER-α) and toxic compounds, including the DDD derivatives. We used molecular docking and molecular dynamics (MD) simulations to explore the possible interaction between mitotane and the ER-α receptor and the induced conformational changes. The ER-α expressing MCF-7 cells were exposed to mitotane with/without tamoxifen, and the cell viability/proliferation was evaluated by MTT assay and direct count. The transient ER-α silencing was performed using two ER-α siRNA (50 nM) and verified by Western blot. MDA-MB-231 cells were used as a negative control. Mitotane showed a similar docking configuration to 17β-estradiol and bisphenol A (BPA) and a significant binding affinity to ER-α. MD simulations showed that mitotane preserves the active conformation of ER-α more than both BPA and Bisphenol C, classifying it as an agonist. Exposure of MCF-7 cells to mitotane led to the concentration-dependent increase of cell viability and proliferation, which was reduced in the presence of tamoxifen and nullified by the transient ER-α knock-down. Integrating bioinformatics approaches with cell biology and pharmacological methods, we demonstrated that mitotane directly binds and activates ER-α.https://www.mdpi.com/2227-9059/9/6/681estrogen receptor αmitotaneadrenocortical carcinomabioinformatics analysis |
| spellingShingle | Elisa Rossini Edoardo Giacopuzzi Fabrizio Gangemi Mariangela Tamburello Deborah Cosentini Andrea Abate Marta Laganà Alfredo Berruti Salvatore Grisanti Sandra Sigala Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α Biomedicines estrogen receptor α mitotane adrenocortical carcinoma bioinformatics analysis |
| title | Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α |
| title_full | Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α |
| title_fullStr | Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α |
| title_full_unstemmed | Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α |
| title_short | Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α |
| title_sort | estrogen like effect of mitotane explained by its agonist activity on estrogen receptor α |
| topic | estrogen receptor α mitotane adrenocortical carcinoma bioinformatics analysis |
| url | https://www.mdpi.com/2227-9059/9/6/681 |
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