Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen
Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5...
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| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/21/5174 |
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| author | Miguel Guerra-Rodríguez Priscila López-Rojas Ángel Amesty Haidée Aranda-Tavío Yeray Brito-Casillas Ana Estévez-Braun Leandro Fernández-Pérez Borja Guerra Carlota Recio |
| author_facet | Miguel Guerra-Rodríguez Priscila López-Rojas Ángel Amesty Haidée Aranda-Tavío Yeray Brito-Casillas Ana Estévez-Braun Leandro Fernández-Pérez Borja Guerra Carlota Recio |
| author_sort | Miguel Guerra-Rodríguez |
| collection | DOAJ |
| description | Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds <b>32</b> and <b>35</b> inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound <b>32</b> regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound <b>35</b> caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds <b>32</b> and <b>35</b> caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound <b>35</b> suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound <b>35</b> showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound <b>35</b> may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment. |
| first_indexed | 2024-03-09T19:12:52Z |
| format | Article |
| id | doaj.art-03a682ebc59a425c9137cfaf7e3a4812 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T19:12:52Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-03a682ebc59a425c9137cfaf7e3a48122023-11-24T04:00:15ZengMDPI AGCancers2072-66942022-10-011421517410.3390/cancers14215174Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of TamoxifenMiguel Guerra-Rodríguez0Priscila López-Rojas1Ángel Amesty2Haidée Aranda-Tavío3Yeray Brito-Casillas4Ana Estévez-Braun5Leandro Fernández-Pérez6Borja Guerra7Carlota Recio8Farmacología Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe Físico s/n, 35016 Las Palmas de Gran Canaria, SpainDepartamento de Química Orgánica, Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna (ULL), Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, SpainDepartamento de Química Orgánica, Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna (ULL), Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, SpainFarmacología Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe Físico s/n, 35016 Las Palmas de Gran Canaria, SpainFarmacología Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe Físico s/n, 35016 Las Palmas de Gran Canaria, SpainDepartamento de Química Orgánica, Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna (ULL), Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, SpainFarmacología Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe Físico s/n, 35016 Las Palmas de Gran Canaria, SpainFarmacología Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe Físico s/n, 35016 Las Palmas de Gran Canaria, SpainFarmacología Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe Físico s/n, 35016 Las Palmas de Gran Canaria, SpainTamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds <b>32</b> and <b>35</b> inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound <b>32</b> regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound <b>35</b> caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds <b>32</b> and <b>35</b> caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound <b>35</b> suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound <b>35</b> showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound <b>35</b> may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.https://www.mdpi.com/2072-6694/14/21/51745-hydroxy-2<i>H</i>-pyrrol-2-onesERantiestrogenbreast cancerendometrial cancersynergism |
| spellingShingle | Miguel Guerra-Rodríguez Priscila López-Rojas Ángel Amesty Haidée Aranda-Tavío Yeray Brito-Casillas Ana Estévez-Braun Leandro Fernández-Pérez Borja Guerra Carlota Recio Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen Cancers 5-hydroxy-2<i>H</i>-pyrrol-2-ones ER antiestrogen breast cancer endometrial cancer synergism |
| title | Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen |
| title_full | Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen |
| title_fullStr | Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen |
| title_full_unstemmed | Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen |
| title_short | Discovery of Highly Functionalized 5-hydroxy-2<i>H</i>-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen |
| title_sort | discovery of highly functionalized 5 hydroxy 2 i h i pyrrol 2 ones that exhibit antiestrogenic effects in breast and endometrial cancer cells and potentiate the antitumoral effect of tamoxifen |
| topic | 5-hydroxy-2<i>H</i>-pyrrol-2-ones ER antiestrogen breast cancer endometrial cancer synergism |
| url | https://www.mdpi.com/2072-6694/14/21/5174 |
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