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1.
Aging (Albany NY) ; 13(12): 16178-16197, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34182538

RESUMO

Tamoxifen (TAM) resistance constitutes a challenge in managing estrogen receptor (ER)α+ breast cancer patients. G-protein-coupled estrogen receptor (GPR30/GPER), which reportedly initiates TAM resistance in ERα+/ GPR30+ breast cancers, is detected in the breast cancer microenvironment, especially cancer associated fibroblasts (CAFs). Herein, considering that GPR30 mediates transcriptional regulation in different cell backgrounds, a microarray strategy was applied in immortalized CAFs derived from primary breast cancer samples, resulting in the identification of 165 GPR30 target genes, among which HMGB1 was confirmed to be upregulated by 17-ß estradiol(E2)- and TAM-triggered GPR30 activation in CAFs. Activated GPR30 increased extracellular HMGB1 secretion by CAFs, which was reduced by blocking PI3K/AKT signaling using G15 or LY294002. GPR30-induced HMGB1 upregulation triggered MEK/ERK signaling, leading to increased autophagic behavior to protect cancer cells from TAM-induced apoptosis, mimicking the recombinant HMGB1-mediated increase in cancer cell resistance potential to TAM. MEK/ERK signaling blockage by U0126 decreased the autophagic behavior and resistance ability of cancer cells to TAM. CAF-expressed GPR30 induced TAM resistance via HMGB1 in vivo. Overall, TAM upregulated HMGB1 expression and secretion in CAFs via GPR30/PI3K/AKT signaling, and the secreted HMGB1 induced autophagy to enhance TAM resistance in MCF-7 cells in an ERK-dependent manner. Thus, targeting GPR30 and downstream cascades may be an effective strategy to attenuate the resistance of ERα-positive breast tumors to endocrine therapy.


Assuntos
Autofagia , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteína HMGB1/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Tamoxifeno/farmacologia , Regulação para Cima , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/genética , Fibroblastos Associados a Câncer/patologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína HMGB1/genética , Humanos , Células MCF-7 , Camundongos Nus , Modelos Biológicos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
Ecotoxicol Environ Saf ; 221: 112453, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186418

RESUMO

Breast cancer (BrCa) as one of the major malignancies threatening women's health worldwide occurs due to the genetic and environmental interactions. Epidemiological studies have suggested that exposure to endocrine disrupting chemicals (EDCs) can elevate the risk of breast cancer. Di-(2-ethylhexyl)-phthalate (DEHP) and bisphenol A (BPA) are known as two typical EDCs. Although several studies have implied that there appear to have adverse effects of exposure to BPA or DEHP alone on breast development, no study to date has demonstrated the exact toxic effect of combined exposure to DEHP and BPA on breast tumorigenesis. In the present study, we performed an in vivo experiment including 160 female Sprague-Dawley (SD) rats, in which 80 rats were randomly allocated to 4 groups including control group given to normal diet, DEHP (150 mg/kg body weight/day), BPA (20 mg/kg body weight/day), and DEHP (150 mg/kg body weight/day) combined with BPA (20 mg/kg body weight/day) by gavage for 30 weeks. Additionally, a DEN/MNU/DHPN (DMD)-induced carcinogenesis animal model was also established to assess their effect on tumor promotion. Namely, the other 80 SD rats were separated into another 4 groups: in addition to DMD initiation each group treated with vehicle, DEHP, BPA and the combination of BPA and DEHP respectively. Our data demonstrated that BPA alone or in combination with DEHP may induce hyperplasia of mammary glands, including the proliferation of ductal epithelial cells and an increase in the number of lobules and acinus after a 30-week exposure. Notably, co-exposure to DEHP and BPA increased the incidence and reduced the latency of mammary tumor, which seemed to enhance the susceptibility of carcinogens-induced tumor. Mechanistically, our results supported the hypothesis that exposure to BPA and DEHP might promote breast cancer dependent on Esr1 and HDAC6 as pivotal factors, and further lead to the activation of oncogene c-Myc. Our study suggested that BPA combined with DEHP facilitate the occurrence of mammary tumors, which contributed to advance our understanding in the complex effects of compound exposure to endocrine disrupting chemicals.


Assuntos
Compostos Benzidrílicos/toxicidade , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Receptor alfa de Estrogênio/metabolismo , Desacetilase 6 de Histona/metabolismo , Neoplasias Mamárias Animais/induzido quimicamente , Fenóis/toxicidade , Animais , Sinergismo Farmacológico , Receptor alfa de Estrogênio/genética , Feminino , Desacetilase 6 de Histona/genética , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Ratos Sprague-Dawley , Ativação Transcricional , Regulação para Cima/efeitos dos fármacos
3.
Molecules ; 26(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064380

RESUMO

The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17ß-hydroxysteroid dehydrogenase type 1 and ß-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and ß-tubulin, which may account for the described effects.


Assuntos
Simulação de Acoplamento Molecular , Oximas/síntese química , Oximas/farmacologia , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Estrona/síntese química , Estrona/química , Estrona/farmacologia , Fluoruracila/farmacologia , Humanos , Concentração Inibidora 50 , Oximas/química
4.
Nat Commun ; 12(1): 3319, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083547

RESUMO

Long noncoding RNAs are widely implicated in diverse disease processes. Nonetheless, their regulatory roles in bone resorption are undefined. Here, we identify lncRNA Nron as a critical suppressor of bone resorption. We demonstrate that osteoclastic Nron knockout mice exhibit an osteopenia phenotype with elevated bone resorption activity. Conversely, osteoclastic Nron transgenic mice exhibit lower bone resorption and higher bone mass. Furthermore, the pharmacological overexpression of Nron inhibits bone resorption, while caused apparent side effects in mice. To minimize the side effects, we further identify a functional motif of Nron. The delivery of Nron functional motif to osteoclasts effectively reverses bone loss without obvious side effects. Mechanistically, the functional motif of Nron interacts with E3 ubiquitin ligase CUL4B to regulate ERα stability. These results indicate that Nron is a key bone resorption suppressor, and the lncRNA functional motif could potentially be utilized to treat diseases with less risk of side effects.


Assuntos
Osteoporose/genética , Osteoporose/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/metabolismo , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Reabsorção Óssea/prevenção & controle , Proteínas Culina/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Fêmur/patologia , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/terapia , RNA Longo não Codificante/administração & dosagem , Ubiquitinação , Regulação para Cima , Microtomografia por Raio-X
5.
Molecules ; 26(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066820

RESUMO

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.


Assuntos
Antineoplásicos/química , Antineoplásicos/metabolismo , Azóis/química , Azóis/metabolismo , Citotoxinas/química , Citotoxinas/metabolismo , Simulação de Acoplamento Molecular/métodos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Azóis/síntese química , Azóis/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/metabolismo , Humanos , Células MCF-7 , Estrutura Molecular , Células PC-3 , Relação Estrutura-Atividade , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia
6.
J Med Chem ; 64(11): 7575-7595, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34056898

RESUMO

The estrogen receptor α (ERα) is identified as an effective target for the treatment of ERα+ breast cancer; thus, discovery of novel selective estrogen receptor degraders (SERDs) are developed as an effective method to overcome the resistance of breast cancer. Herein, the hot-spot residues for protein-ligand interaction between SERDs and ERα are analyzed by molecular dynamic simulation technology, focusing on the hot-spot residues for four series of designed and synthesized SERDs. SAR studies revealed that while the acrylic acid moiety of AZD9496 is scaffold hopping into benzoic acid, compound D24 exhibits potent binding affinity with ERα, good degradation efficacy of ERα, and inhibitory effect against the MCF-7 breast cancer cell line. Besides, D24 also displays good antitumor efficacy in the MCF-7 human breast cancer xenograft model in vivo, favorable pharmacokinetic properties, excellent druggability, and good safety property, making D24 as a promising drug candidate of SERD for further evaluation.


Assuntos
Antineoplásicos/química , Ácido Benzoico/química , Receptor alfa de Estrogênio/metabolismo , Administração Oral , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ácido Benzoico/metabolismo , Ácido Benzoico/farmacologia , Ácido Benzoico/uso terapêutico , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Desenho de Fármacos , Receptor alfa de Estrogênio/química , Feminino , Meia-Vida , Humanos , Ligantes , Células MCF-7 , Camundongos , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Termodinâmica , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Toxicology ; 457: 152805, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33961950

RESUMO

Niclosamide (NIC), a helminthic drug used widely for controlling schistosomiasis, can reportedly disrupt the endocrine system. However, its underlying mechanisms are still unclear. In this study, we revealed the potential endocrine disruption mechanism of NIC by activating estrogen receptors (ERs) and estrogen-related receptors (ERRs). The binding potency of NIC with ERα, ERß and ERRγ were determined by fluorescence competitive binding assays, which shows an IC50 (the concentration of NIC needed to displace 50 % of the probe from the receptor) of 90 ± 4.1, 10 ± 1.7 nM and 0.59 ± 0.07 nM respectively. The IC50 for ERRγ is the lowest one among the three detected receptors, which is three orders of magnitude lower than the known agonist GSK4716.The transcriptional activities of NIC on ERs and ERRs were detected by MVLN cells (stably transfected with ERs reporter gene) and HeLa cells (transiently transfected with ERRs reporter gene)-based luciferase reporter gene assay. The lowest observable effective concentration (LOEC) ranked as follows: ERRγ (0.5 nM) < ERRα (10 nM) < ERs (100 nM). The maximum observed induction rate for ERRγ (294 %) was higher than that for ERRα (191 %). The maximum observed induction rate of NIC for ERs was 30 % relative to 17ß-estradiol. In addition, we simulated the interactions of NIC with ERs and ERRs by molecular docking. NIC could dock into the ligand binding pockets of ERs and ERRs and form hydrogen bonds with different amino acids. The binding energy ranked as follows: ERRγ (-8.90 kcal/mol) < ERß (-7.57 kcal/mol) < ERRα (-7.15 kcal/mol) < ERα (-6.53 kcal/mol), which implied that NIC bound to ERRγ with higher binding affinity than the other receptors. Overall, we clarify that ERRγ might be the dominant target for NIC in cells rather than ERRα and ERs. We reveal potential novel mechanisms for the endocrine disruption effects of NIC by activating both ERRs and ERs at environmentally-related nanomolar levels.


Assuntos
Disruptores Endócrinos/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Niclosamida/metabolismo , Receptores de Estrogênio/metabolismo , Anticestoides/metabolismo , Anticestoides/toxicidade , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Células HeLa , Humanos , Células MCF-7 , Niclosamida/toxicidade , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína
8.
Biomed Res Int ; 2021: 6658321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937407

RESUMO

A thin endometrium affects the success of assisted reproduction due to low endometrial receptivity. Acupuncture improves endometrial receptivity and promotes the formation of pinopodes, the ultrastructure marker implantation window. However, the specific underlying mechanisms remain unclear. In this study, the efficacy of acupuncture treatment and its underlying mechanism were investigated by analyzing pregnancy rate, pinopode formation, and related molecular markers in thin endometrium model rats. Absolute ethanol (95%) was injected into the uteruses of female Sprague-Dawley rats to construct a thin endometrium model. In this model, acupuncture stimulation at EX-CA1, SP6, and CV4 ameliorated the pregnancy rate. Significantly increased embryo implantation, endometrial thickness, numbers of glands, and blood vessels were observed in the electroacupuncture (EA) group compared to the model group. The number of pinopodes in the EA group was abundant, with a shape similar to that of the control group. Additionally, significantly higher expression levels of pinopode-related markers, including integrin αvß3, homeobox A10 (HOXA10), heparin-binding EGF-like growth factor (HBEGF), estrogen receptor alpha (ERα), and progesterone receptor (PR), were observed in the EA group than those in the model group. In conclusion, EA had a positive effect on the endometrial receptivity of thin endometrium model rats by improving pinopode formation through multiple molecular targets.


Assuntos
Eletroacupuntura , Endométrio/metabolismo , Endométrio/patologia , Resultado da Gravidez , Animais , Modelos Animais de Doenças , Implantação do Embrião , Endométrio/ultraestrutura , Receptor alfa de Estrogênio/metabolismo , Ciclo Estral , Feminino , Masculino , Gravidez , Ratos Sprague-Dawley , Receptores de Progesterona/metabolismo
9.
Gene ; 791: 145726, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34010704

RESUMO

Traditional herbal medicine (THM) comprises a vast number of natural compounds. Most of them are metabolized into different structures after administration, which makes the clarification of THM's mode of action more complicated. To evaluate the biological activities of those components and metabolites, in silico simulation technology is helpful. We focused on mixed-solvent molecular dynamics (MD) simulation for druggability assessment of natural products. Mixed-solvent MD is an in silico simulation method for the exploration of ligand-binding sites on target proteins, which uses water and an organic molecule mixture. The selection of organic small molecules is an important factor for predicting the characteristics of natural products. In this study, we used the known crystal structure of estrogen receptors with genistein as a test case and explored fragments reflecting the characteristics of natural products. We found that structures with a 4-pyrone structure are more often included in the natural products database compared with the DrugBank database, and we selectively detected the known-binding sites of estrogen receptor α and ß. The results indicate that the 4-pyrone structure might be promising for predicting the protein druggability of flavonoids. Additionally, mixed-solvent MD simulation discriminates the selectivity of genistein between estrogen receptor ß and α, indicating that the simulation can be evaluated using indices that differ from those of traditional ligand docking. Although this approach is still in its early stages, it has the potential to provide valuable information for understanding the diverse biological activities of natural products.


Assuntos
Medicina Tradicional/métodos , Simulação de Acoplamento Molecular/métodos , Plantas Medicinais/química , Animais , Sítios de Ligação/efeitos dos fármacos , Produtos Biológicos/química , Simulação por Computador , Bases de Dados Factuais , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Receptor beta de Estrogênio/metabolismo , Flavonoides/química , Genisteína/farmacologia , Humanos , Ligantes , Simulação de Dinâmica Molecular , Plantas Medicinais/metabolismo , Ligação Proteica/efeitos dos fármacos , Receptores de Estrogênio/química
10.
Jpn J Clin Oncol ; 51(7): 1051-1058, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33893504

RESUMO

BACKGROUND: Papillary thyroid cancer cells can express oestrogen receptor alpha, which is encoded by the ESR1 gene and may bind to oestrogen to induce the occurrence and development of papillary thyroid cancer. The BRAFV600E mutation is also an important biomarker for the occurrence and progression of papillary thyroid cancer. However, the association between the BRAFV600E mutation and oestrogen receptor alpha expression has not been identified. This study aims to investigate the association between ESR1 expression and the BRAFV600E mutation and its clinical significance. METHODS: Oestrogen receptor alpha and BRAFV600E proteins were detected by immunohistochemical staining of formalin-fixed paraffin-embedded thyroid tissues from 1105 patients with papillary thyroid cancer at our institution. Messenger RNA expression counts of ESR1 and clinicopathologic information were obtained from The Cancer Genome Atlas database. RESULTS: Oestrogen receptor alpha protein expression was significantly associated with BRAFV600E protein. The positive rate of oestrogen receptor alpha protein in papillary thyroid cancer patients was significantly higher in males, younger patients and patients with the multifocal type. In papillary thyroid cancer patients with positive BRAFV600E protein, oestrogen receptor alpha expression was significantly correlated with central lymph node metastasis. Data from the The Cancer Genome Atlas database also suggested that the ESR1 messenger RNA level was associated with the BRAFV600E mutation. Furthermore, classification analysis performed according to a tree-based classification method demonstrated that higher ESR1 messenger RNA expression indicated poorer overall survival in papillary thyroid cancer patients with the BRAFV600E mutation. CONCLUSIONS: The percentage of BRAFV600E mutations is increased in patients with higher ESR1 messenger RNA levels, and the BRAFV600E protein might be co-expressed with oestrogen receptor alpha, which could be an indicator of cervical lymph node metastasis and poor overall survival in patients with papillary thyroid cancer.


Assuntos
Receptor alfa de Estrogênio , Proteínas Proto-Oncogênicas B-raf , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo
11.
Anat Rec (Hoboken) ; 304(6): 1185-1193, 2021 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1184569

RESUMO

Estrogen is an important hormone for health in both genders. It is indispensable to glucose homeostasis, immune robustness, bone health, cardiovascular health, and neural functions. The main way that estrogen acts in the cells is through estrogen receptors (ERs). The presence of specific estrogen receptors is required for estrogen to have its characteristic ubiquitous action in almost all tissues. Estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) are the major isoforms of estrogen that are highly specific in humans and enable selective hormonal actions in different tissues. This article reviews some of the observed estrogen actions and effects in different tissues and cells through these specific receptors. This ubiquitous, almost ordinary hormone may reveal itself as a significant factor that helped us to better understand the complexity of the human immune system response against respiratory infections, including the COVID-19, and especially in the current state of this painful pandemic.


Assuntos
COVID-19/imunologia , Receptor alfa de Estrogênio/imunologia , Receptor beta de Estrogênio/imunologia , Sistema Imunitário/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Humanos , Sistema Imunitário/metabolismo , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Sistema Respiratório/metabolismo , SARS-CoV-2/metabolismo
12.
J Med Chem ; 64(9): 5766-5786, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33904307

RESUMO

(E/Z)-3-(4-((E)-1-(4-Hydroxyphenyl)-2-phenylbut-1-enyl)phenyl)acrylic acid (GW7604) as a derivative of (Z)-4-hydroxytamoxifen (4-OHT) was linked by diaminoalkane spacers to molecules that are known binders to the coactivator binding site (benzimidazole or thioxo-quinazolinone scaffolds). With this modification, an optimization of the pharmacological profile was achieved. The most active thioxo-quinazolinone derivative 16 showed extraordinarily high affinity to the estrogen receptor (ER) ß (RBA = 110%), inhibited effectively the coactivator recruitment (IC50 = 20.88 nM (ERα) and 28.34 nM (ERß)), acted as a pure estradiol (E2) antagonist in a transactivation assay (IC50 = 18.5 nM (ERα) and 7.5 nM (ERß)), and downregulated the ERα content in MCF-7 cells with an efficacy of 60% at 1 µM. The cytotoxicity was restricted to hormone-dependent MCF-7 (IC50 = 4.2 nM) and tamoxifen-resistant MCF-7TamR cells (IC50 = 476.6 nM). The compounds bearing a thioxo-quinazolinone moiety can therefore be assigned as pure E2-antagonistic selective ER degraders/downregulators. By contrast, the benzimidazole derivatives acted solely as pure antagonists without degradation of the ER.


Assuntos
Acrilatos/química , Receptor alfa de Estrogênio/agonistas , Tamoxifeno/análogos & derivados , Acrilatos/metabolismo , Acrilatos/farmacologia , Benzimidazóis/química , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Sítios de Ligação , Ligação Competitiva , Dimerização , Regulação para Baixo/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Humanos , Ligantes , Células MCF-7 , Simulação de Acoplamento Molecular , Quinazolinonas/química , Quinazolinonas/metabolismo , Quinazolinonas/farmacologia , Relação Estrutura-Atividade , Tamoxifeno/química , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia , Ativação Transcricional/efeitos dos fármacos
13.
Anat Rec (Hoboken) ; 304(6): 1185-1193, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33856123

RESUMO

Estrogen is an important hormone for health in both genders. It is indispensable to glucose homeostasis, immune robustness, bone health, cardiovascular health, and neural functions. The main way that estrogen acts in the cells is through estrogen receptors (ERs). The presence of specific estrogen receptors is required for estrogen to have its characteristic ubiquitous action in almost all tissues. Estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) are the major isoforms of estrogen that are highly specific in humans and enable selective hormonal actions in different tissues. This article reviews some of the observed estrogen actions and effects in different tissues and cells through these specific receptors. This ubiquitous, almost ordinary hormone may reveal itself as a significant factor that helped us to better understand the complexity of the human immune system response against respiratory infections, including the COVID-19, and especially in the current state of this painful pandemic.


Assuntos
COVID-19/imunologia , Receptor alfa de Estrogênio/imunologia , Receptor beta de Estrogênio/imunologia , Sistema Imunitário/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Humanos , Sistema Imunitário/metabolismo , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Sistema Respiratório/metabolismo , SARS-CoV-2/metabolismo
14.
Mar Drugs ; 19(4)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920324

RESUMO

Menopause, caused by decreases in estrogen production, results in symptoms such as facial flushing, vaginal atrophy, and osteoporosis. Although hormone replacement therapy is utilized to treat menopausal symptoms, it is associated with a risk of breast cancer development. We aimed to evaluate the estrogenic activities of Spartina anglica (SA) and its compounds and identify potential candidates for the treatment of estrogen reduction without the risk of breast cancer. We evaluated the estrogenic and anti-proliferative effects of extracts of SA and its compounds in MCF-7 breast cancer cells. We performed an uterotrophic assay using an immature female rat model. Among extracts of SA, belowground part (SA-bg-E50) had potent estrogenic activity. In the immature female rat model, the administration of SA-bg-E50 increased uterine weight compared with that in the normal group. Among the compounds isolated from SA, 1,3-di-O-trans-feruloyl-(-)-quinic acid (1) had significant estrogenic activity and induced phosphorylation at serine residues of estrogen receptor (ER)α. All extracts and compounds from SA did not increase MCF-7 cell proliferation. Compound 1 is expected to act as an ERα ligand and have estrogenic effects, without side effects, such as breast cancer development.


Assuntos
Fitoestrógenos/farmacologia , Extratos Vegetais/farmacologia , Poaceae/metabolismo , Útero/efeitos dos fármacos , Animais , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Células MCF-7 , Estrutura Molecular , Tamanho do Órgão , Fitoestrógenos/isolamento & purificação , Fitoestrógenos/toxicidade , Componentes Aéreos da Planta/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Raízes de Plantas/metabolismo , Poaceae/crescimento & desenvolvimento , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Útero/crescimento & desenvolvimento , Útero/metabolismo
15.
Toxicol Lett ; 345: 24-33, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33857583

RESUMO

As demonstrated for bisphenol AF (BPAF), the electrostatic halogen bond based on the London dispersion force of halogen atoms was found to be a major driving force of their bifunctional ERα-agonist and ERß-antagonist activities. Because similar electronic effects are anticipated for hydrocarbon groups (alkyl or aryl groups), we hypothesized that bisphenol compounds consisting of such groups also work bifunctionally. In the present study, we examined bisphenol AP (BPAP), B (BPB), and Z (BPZ). After recognizing their considerably strong receptor binding affinities, we evaluated the abilities of BPAP, BPB, and BPZ to activate ERα and ERß in a luciferase reporter gene assay. These bisphenols were fully active for ERα but completely inactive for ERß. When we examined their inhibitory activities for 17ß-estradiol in ERß by two different qualitative and quantitative analytical methods, we found that those bisphenols worked as definite antagonists. Consequently, they were established as bifunctional ERα-agonists and ERß-antagonists. The present structure-activity analyses revealed that the dispersion force works not only on the halogens but also on the hydrocarbon groups, and that it is a major driving force of bifunctional ERα-agonist and ERß-antagonist activities.


Assuntos
Compostos Benzidrílicos/toxicidade , Cicloexanos/toxicidade , Disruptores Endócrinos/toxicidade , Antagonistas de Estrogênios/toxicidade , Receptor alfa de Estrogênio/agonistas , Receptor beta de Estrogênio/antagonistas & inibidores , Estrogênios/toxicidade , Fenóis/toxicidade , Compostos Benzidrílicos/química , Compostos Benzidrílicos/metabolismo , Sítios de Ligação , Cicloexanos/química , Cicloexanos/metabolismo , Disruptores Endócrinos/química , Disruptores Endócrinos/metabolismo , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/química , Estrogênios/metabolismo , Células HeLa , Humanos , Estrutura Molecular , Fenóis/química , Fenóis/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
16.
J Med Chem ; 64(8): 5049-5066, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33844532

RESUMO

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.


Assuntos
DNA/química , Receptor alfa de Estrogênio/metabolismo , Bibliotecas de Moléculas Pequenas/química , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Click , DNA/metabolismo , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Feminino , Meia-Vida , Humanos , Indóis/química , Indóis/metabolismo , Cinética , Camundongos , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nature ; 593(7857): 108-113, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33790464

RESUMO

Innate vocal sounds such as laughing, screaming or crying convey one's feelings to others. In many species, including humans, scaling the amplitude and duration of vocalizations is essential for effective social communication1-3. In mice, female scent triggers male mice to emit innate courtship ultrasonic vocalizations (USVs)4,5. However, whether mice flexibly scale their vocalizations and how neural circuits are structured to generate flexibility remain largely unknown. Here we identify mouse neurons from the lateral preoptic area (LPOA) that express oestrogen receptor 1 (LPOAESR1 neurons) and, when activated, elicit the complete repertoire of USV syllables emitted during natural courtship. Neural anatomy and functional data reveal a two-step, di-synaptic circuit motif in which primary long-range inhibitory LPOAESR1 neurons relieve a clamp of local periaqueductal grey (PAG) inhibition, enabling excitatory PAG USV-gating neurons to trigger vocalizations. We find that social context shapes a wide range of USV amplitudes and bout durations. This variability is absent when PAG neurons are stimulated directly; PAG-evoked vocalizations are time-locked to neural activity and stereotypically loud. By contrast, increasing the activity of LPOAESR1 neurons scales the amplitude of vocalizations, and delaying the recovery of the inhibition clamp prolongs USV bouts. Thus, the LPOA disinhibition motif contributes to flexible loudness and the duration and persistence of bouts, which are key aspects of effective vocal social communication.


Assuntos
Hipotálamo/fisiologia , Vocalização Animal/fisiologia , Animais , Corte , Receptor alfa de Estrogênio/metabolismo , Feminino , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/fisiologia , Área Pré-Óptica/citologia , Área Pré-Óptica/fisiologia , Sinapses/metabolismo , Fatores de Tempo , Ondas Ultrassônicas
18.
Breast Cancer Res Treat ; 187(2): 375-386, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33893909

RESUMO

PURPOSE: The majority of breast cancers are estrogen receptor (ERα) positive making endocrine therapy a mainstay for these patients. Unfortunately, resistance to endocrine therapy is a common occurrence. Fatty acid synthase (FASN) is a key enzyme in lipid biosynthesis and its expression is commensurate with tumor grade and resistance to numerous therapies. METHODS: The effect of the FASN inhibitor TVB-3166 on ERα expression and cell growth was characterized in tamoxifen-resistant cell lines, xenografts, and patient explants. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by Western blotting after treatment with TVB-3166 with or without the addition of palmitate or BAPTA. RESULTS: TVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant cells compared to the parental cells. Additionally, TVB-3166 significantly inhibited tamoxifen-resistant breast tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine-resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress. CONCLUSION: Our preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for the treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine-resistant breast cancer should be considered.


Assuntos
Neoplasias da Mama , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Graxo Sintases , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Tamoxifeno/farmacologia
19.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805656

RESUMO

17ß-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.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Clotrimazol/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Imidazóis/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antifúngicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Descoberta de Drogas , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteólise , Transdução de Sinais , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
20.
Molecules ; 26(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799482

RESUMO

Flavonoids are plant bioactives that are recognized as hormone-like polyphenols because of their similarity to the endogenous sex steroids 17ß-estradiol and testosterone, and to their estrogen- and androgen-like activity. Most efforts to verify flavonoid binding to nuclear receptors (NRs) and explain their action have been focused on ERα, while less attention has been paid to other nuclear and non-nuclear membrane androgen and estrogen receptors. Here, we investigate six flavonoids (apigenin, genistein, luteolin, naringenin, quercetin, and resveratrol) that are widely present in fruits and vegetables, and often used as replacement therapy in menopause. We performed comparative computational docking simulations to predict their capability of binding nuclear receptors ERα, ERß, ERRß, ERRγ, androgen receptor (AR), and its variant ART877A and membrane receptors for androgens, i.e., ZIP9, GPRC6A, OXER1, TRPM8, and estrogens, i.e., G Protein-Coupled Estrogen Receptor (GPER). In agreement with data reported in literature, our results suggest that these flavonoids show a relevant degree of complementarity with both estrogen and androgen NR binding sites, likely triggering genomic-mediated effects. It is noteworthy that reliable protein-ligand complexes and estimated interaction energies were also obtained for some suggested estrogen and androgen membrane receptors, indicating that flavonoids could also exert non-genomic actions. Further investigations are needed to clarify flavonoid multiple genomic and non-genomic effects. Caution in their administration could be necessary, until the safe assumption of these natural molecules that are largely present in food is assured.


Assuntos
Androgênios/metabolismo , Núcleo Celular/metabolismo , Estrogênios/metabolismo , Flavonoides/metabolismo , Ligação Proteica/fisiologia , Receptores de Superfície Celular/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Humanos , Simulação de Acoplamento Molecular , Receptores de Estrogênio , Testosterona/metabolismo
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