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1.
Anticancer Res ; 40(2): 857-864, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32014929

RESUMO

AIM: The purpose of this study was to determine the level of adherence to adjuvant aromatase inhibitor (AI) therapy and factors associated with non-adherence among Hispanic/Latino women with hormonal receptor-positive breast cancer (BC) treated at an academic center at the American-Mexican border city of El Paso, TX. PATIENTS AND METHODS: Institutional Review Board approval was obtained in this cross-sectional study using the validated Morisky Medication Adherence Scale to assess patient adherence to AI therapy. Patients diagnosed with stage I-III hormonal receptor-positive, human epidermal growth factor receptor 2-negative BC who were on adjuvant AIs therapy were recruited from the Texas Tech University Health Sciences Center El Paso breast clinic. RESULTS: Between September 2017 and August 2018, 122 consecutive patients were enrolled; 119 were analyzed, three were lost to follow up. The mean age was 61.6±9.4 years, and 109 (91.6%) self-identified as Hispanic/Latino. A total of 58% reported an annual income of $15,000 or less. Overall, 40.3% had completed eighth grade or less education, 31.9% high school, and 12% had obtained a technical degree. The majority of patients (56%) had either a medium (45%) or a low level of adherence (11%). High adherence was noted in 44% of participants. Seven (5.6%) patients scored 2 or below on a 4-point scale for intentional adherence, and 18 (13.5%) scored 2 or below on a 4-point scale for unintentional adherence. CONCLUSION: These data suggest that the majority of Hispanic/Latino women with breast cancer have medium or low levels of adherence to therapy with AIs. Factors associated with medium and low adherence were unintentional (forgetfulness), but also included intentional factors, such as avoidance of adverse effects and delays with obtaining refills (cost-related nonadherence).


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Inibidores da Aromatase/farmacologia , Estudos Transversais , Feminino , Hispano-Americanos , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Inquéritos e Questionários
2.
Medicine (Baltimore) ; 99(2): e18550, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914031

RESUMO

BACKGROUND: Adjuvant endocrine therapy is a vital portion of postoperative comprehensive treatment for breast cancer patients. In recent years, studies have shown that endocrine therapy has a certain impact on the serum lipids of breast cancer patients, and the changes of lipid profiles may bring a series of problems. However, very few studies focus on this issue to date. The results of these studies are inconsistent, and the influence of different adjuvant endocrine modalities on lipid profiles still remains controversial. In order to better explore this issue, we conduct this network meta-analysis. METHOD: The protocol followed preferred reporting items for systematic reviews and meta-analyses protocols. Three main databases (PubMed, Embase, and the Cochrane Library) will be searched systematically for eligible randomized controlled trials without language restriction. In addition, a manual search of the references of relevant published studies will also be considered. Two reviewers will conduct studies selection, data extraction, and risk of bias assessment independently. The primary outcome is the variation of biochemical parameters - the serum lipid profiles (cholesterol, triglyceride, high-density lipoprotein, low low-density lipoprotein). RESULTS: The results will provide useful information about the side effects of different adjuvant endocrine drugs on lipid profiles in postoperative breast cancer patients (estrogen receptor-positive and/or progesterone receptor-positive). CONCLUSION: The findings of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019129850.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Lipídeos/sangue , Anastrozol/farmacologia , Anastrozol/uso terapêutico , Androstadienos/farmacologia , Androstadienos/uso terapêutico , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Quimioterapia Adjuvante , Humanos , Letrozol/farmacologia , Letrozol/uso terapêutico , Meta-Análise em Rede , Projetos de Pesquisa , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Toremifeno/farmacologia , Toremifeno/uso terapêutico
3.
Eur J Med Chem ; 185: 111815, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732252

RESUMO

In order to identify new aromatase enzyme inhibitors, thirty aryl sulfonamide derivatives containing an indole nucleus have been synthesized. The enzyme inhibition assay showed that four compounds inhibit aromatase in the sub-micromolar range. Loading concentrations of these four compounds were afterwards tested for cell viability and cytotoxicity on MCF7 human breast cancer cells, revealing a time- and dose-dependent decrease of active metabolizing cells over the time of the culture (0-72 h), starting from a concentration of 100 µM. Likewise LDH released raised up to 40% at early time of exposures (24 h). Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Indóis/farmacologia , Sulfonamidas/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
4.
J Steroid Biochem Mol Biol ; 195: 105486, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31557516

RESUMO

Estrogen receptor-positive (ER+) breast cancers require estrogens for their growth. Aromatase inhibitors (AIs) are considered the first-line therapy for this type of tumours. Despite the well-established clinical benefit of this therapy, the search for novel potent AIs that present higher efficacy and fewer side effects is still demanded. Thus, taking into account the known interactions of the natural substrate, androstenedione, within the aromatase active-site, a range of new steroidal compounds have been designed, synthesized and studied by our group. In this work, it was evaluated in MCF-7aro, an ER+ breast cancer cell line that overexpress aromatase, the anti-aromatase efficacy and the biological effects of eight new AIs: 6α-methyl-5α-androst-3-en-17-one (1a), 6α-methyl-3α,4α-epoxy-5α-androstan-17-one (3a), 6α-methylandrost-4-ene-3,17-dione (9), 6α-allylandrosta-1,4-diene-3,17-dione (13), 6α-allylandrost-4-ene-3,17-dione (15), 6α-allylandrost-4-en-17-one (17), 6ß-hydroxyandrost-4-ene-3,17-dione (19) and 6α-hydroxyandrost-4-ene-3,17-dione (20). Their anti-cancer properties were elucidated, as well as, the dependence of their mechanism of action on aromatase inhibition and/or on steroid receptors modulation, such as estrogen and androgen receptors, which are key targets for this type of cancer. Results demonstrate that the studied AIs present high anti-aromatase activity, disrupt MCF-7aro cell cycle progression and induce apoptosis, through the mitochondrial pathway. Compounds 1a, 3a, 9, 13, 15 and 17 exhibited an aromatase-dependent effect on cells and, interestingly, steroids 9 and 13 displayed the ability to decrease aromatase protein levels without affecting CYP19A1 mRNA levels. Furthermore, the effects of compounds 1a, 3a and 15 were dependent on ER and on AR modulation, whereas compounds 9 and 19 were only dependent on AR modulation. From a clinical point of view, these actions can be considered as a therapeutic advantage for this type of tumours. Thus, new promising AIs that impair ER+ breast cancer cell growth, by acting on aromatase, and even, on ER and AR were discovered. Furthermore, new insights on the most favourable structural modifications in the steroidal core structure were provided, helping to a more rational drug design of new and potent AIs.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Receptores Androgênicos/metabolismo , Aromatase/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , RNA Mensageiro/metabolismo
5.
Mater Sci Eng C Mater Biol Appl ; 105: 110099, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546395

RESUMO

Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.


Assuntos
Androstadienos , Antineoplásicos Fitogênicos , Inibidores da Aromatase , Neoplasias da Mama , Hesperidina , Nanocápsulas , Albuminas/química , Albuminas/farmacocinética , Albuminas/farmacologia , Androstadienos/química , Androstadienos/farmacocinética , Androstadienos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Boro/química , Boro/farmacocinética , Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Hesperidina/química , Hesperidina/farmacocinética , Hesperidina/farmacologia , Humanos , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/farmacologia
6.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510070

RESUMO

A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated pathways underlying the modulation of reactive microglia. In the present work, the TSPO activation was explored in an in vitro human primary microglia model (immortalized C20 cells) under inflammatory stimulus. Two different approaches were used with the aim to (i) pharmacologically amplify or (ii) silence, by the lentiviral short hairpin RNA, the TSPO physiological function. In the TSPO pharmacological stimulation model, the synthetic steroidogenic selective ligand XBD-173 attenuated the activation of microglia. Indeed, it reduces and increases the release of pro-inflammatory and anti-inflammatory cytokines, respectively. Such ligand-induced effects were abolished when C20 cells were treated with the steroidogenesis inhibitor aminoglutethimide. This suggests a role for neurosteroids in modulating the interleukin production. The highly steroidogenic ligand XBD-173 attenuated the neuroinflammatory response more effectively than the poorly steroidogenic ones, which suggests that the observed modulation on the cytokine release may be influenced by the levels of produced neurosteroids. In the TSPO silencing model, the reduction of TSPO caused a more inflamed phenotype with respect to scrambled cells. Similarly, during the inflammatory response, the TSPO silencing increased and reduced the release of pro-inflammatory and anti-inflammatory cytokines, respectively. In conclusion, the obtained results are in favor of a homeostatic role for TSPO in the context of dynamic balance between anti-inflammatory and pro-inflammatory mediators in the human microglia-mediated inflammatory response. Interestingly, our preliminary results propose that the TSPO expression could be stimulated by NF-κB during activation of the inflammatory response.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Purinas/farmacologia , Interferência de RNA , Receptores de GABA/metabolismo , Aminoglutetimida/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores da Aromatase/farmacologia , Sequência de Bases , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Citocinas/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/farmacologia , Microglia/metabolismo , NF-kappa B/metabolismo , Fenótipo , Receptores de GABA/genética
7.
Recenti Prog Med ; 110(7): 347-355, 2019.
Artigo em Italiano | MEDLINE | ID: mdl-31379370

RESUMO

LHRH analogues (LHRHa) are used in the treatment of breast cancer that occurs in young women. Amenorrhoea induced by chemotherapy correlates with a reduced risk of recurrence disease. In premenopausal women, analogous LHRHs are used to suppress ovarian estrogen production, raising estrogen hormone levels to post-menopausal values and improving patient outcomes. Two large clinical studies have investigated the role of complete estrogen blockage in adjuvant hormonal treatment of premenopausal patients. Both studies showed the clinical benefit of ovarian suppression treatment, mainly associated with non-steroidal aromatase inhibitor exemestane in high-risk patients. In the recent years, hormonal treatments made available in clinical practice have considerably prolonged the median survival of patients suffering from endocrine-responsive metastatic breast cancer. Even in the premenopausal setting, CDK4/6 inhibitors in association with endocrine therapy have shown a marked improvement in patient outcomes. The safety and efficacy of this new class of drugs demonstrated in the MONALEESA-7 study in premenopausal women and in the premenopausal subgroups of the PALOMA-3 and MONARCH 2 studies support the use of hormone therapy and analogous LHRH combined with CDK 4/6 inhibitor in patients in premenopausal. Finally, LHRH analogues have been extensively studied in strategies for maintaining ovarian function and fertility preservation during adjuvant chemotherapy in younger patients.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Pré-Menopausa , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Feminino , Preservação da Fertilidade , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos
8.
Anal Bioanal Chem ; 411(26): 7005-7013, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31440781

RESUMO

Estrogens are key factors in the development of the estrogen receptor-positive (ER+) breast cancer. Estrogens, estrone (E1), and estradiol (E2) production is achieved by aromatase, a cytochrome P450 enzyme that has androgens, androstenedione (AD), and testosterone (T) as substrates. Nowadays, third-generation aromatase inhibitors (AIs) are considered the gold-standard treatment for ER+ breast cancer in postmenopausal women as well as in premenopausal women with ovary ablation. Aromatase activity assessment still relies on radiometric assays that are expensive, hazardous, and non-environmentally friendly. Thus, in order to overcome these disadvantages, a new methodology was developed to evaluate aromatase activity, based on dispersive liquid-liquid microextraction (DLLME) followed by gas chromatography-mass spectrometry (GC-MS). The enzymatic reaction was carried out in human placental microsomes, using AD as substrate, and the anti-aromatase activity was measured by determining the conversion percentage of AD into E1 (ratio E1/AD) using isotopic analogues as internal standards. The method showed good linearity (r2 = 0.9908 for AD and 0.9944 for E1), high accuracy (more than 74% for AD and more than 66% for E1), high extraction efficiency, and good intra-day and inter-day precision (below 14%, 4 levels). In this work, the IC50 values of the third-generation AIs, anastrozole, letrozole, and exemestane, obtained from the radiometric assay are also compared, and similar IC50 values are described. This method is a good alternative to the current radiometric assay, being fast and sensitive with a good extraction efficiency, accuracy, and recovery. In addition, it may be applied for the evaluation of the anti-aromatase activity of new potential AIs. Graphical abstract.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Microssomos/enzimologia , Aromatase/análise , Ensaios Enzimáticos/métodos , Feminino , Humanos , Microextração em Fase Líquida/métodos , Placenta/enzimologia , Gravidez
9.
Nat Commun ; 10(1): 3778, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439835

RESUMO

MCF7 cells acquire estrogen-independent proliferation after long-term estrogen deprivation (LTED), which recapitulates endocrine therapy resistance. LTED cells can become primed for apoptosis, but the underlying mechanism is largely unknown. We previously reported that Eleanor non-coding RNAs (ncRNAs) upregulate the ESR1 gene in LTED cells. Here, we show that Eleanors delineate the topologically associating domain (TAD) of the ESR1 locus in the active nuclear compartment of LTED cells. The TAD interacts with another transcriptionally active TAD, which is 42.9 Mb away from ESR1 and contains a gene encoding the apoptotic transcription factor FOXO3. Inhibition of a promoter-associated Eleanor suppresses all genes inside the Eleanor TAD and the long-range interaction between the two TADs, but keeps FOXO3 active to facilitate apoptosis in LTED cells. These data indicate a role of ncRNAs in chromatin domain regulation, which may underlie the apoptosis-prone nature of therapy-resistant breast cancer cells and could be good therapeutic targets.


Assuntos
Apoptose/genética , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , RNA não Traduzido/metabolismo , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Apoptose/efeitos dos fármacos , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Sítios de Ligação/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Cromatina/genética , Cromatina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Loci Gênicos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Regiões Promotoras Genéticas/genética , Regulação para Cima
10.
Life Sci ; 232: 116640, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31295470

RESUMO

INTRODUCTION AND AIM: Polycystic ovary syndrome is one of the most common causes of female infertility, affecting 5-10% of the population. Women with PCOS manifest hyperandrogenism, hyperinsulinemia, low-grade systemic inflammation, and polycystic ovaries. Unfortunately, current available medications are only symptomatic without relevant reported treatment. Therefore, a pressing need for alternative safe approaches is necessitated. To this end, the present study is designed to investigate therapeutic merits of the edible plant: Ocimum kilimandscharicum (Ok), in a letrozole PCOS rat model, and compare it to metformin. MATERIAL AND METHODS: PCOS rats were treated with Ok total extract and its different fractions at 100 mg/kg orally for 10 consecutive days. Moreover, phytochemical characterization was applied using HPLC/PDA/ESI-MS to identify different secondary metabolites in the bioactive fractions. KEY FINDINGS: Results revealed that the total extract (Ok) and ethyl acetate (EA) fraction improved insulin sensitivity and restored normal hormonal and lipid profiles as well as normal morphological structure of the reproductive system. Furthermore, elevation of SOD and reduction of VEGF levels in comparison with metformin were recorded. SIGNIFICANCE: These results suggest that Ok extract and EA fraction halt letrozole-induced reproductive dysfunctions and restore normal morphological and physiological functions in PCOS rats, even superior to metformin.


Assuntos
Inibidores da Aromatase/farmacologia , Hipoglicemiantes/farmacologia , Letrozol/farmacologia , Metformina/farmacologia , Ocimum/química , Ovário/efeitos dos fármacos , Ovário/fisiopatologia , Extratos Vegetais/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Idoso , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Modelos Animais de Doenças , Estrogênios/sangue , Estro , Feminino , Glicosídeos/metabolismo , Humanos , Hidroxibenzoatos/metabolismo , Insulina/sangue , Tamanho do Órgão/efeitos dos fármacos , Ovário/patologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Síndrome do Ovário Policístico/fisiopatologia , Progesterona/sangue , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Testosterona/sangue , Triglicerídeos/sangue , Útero/efeitos dos fármacos
11.
Int J Pharm Compd ; 23(4): 325-339, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31315085

RESUMO

This analysis was designed to determine the efficacy of anastrozole, an aromatase inhibitor, combined with testosterone in a subcutaneous implant in preventing elevated estradiol levels and the subsequent side effects of excess estrogen associated with testosterone therapy. It also allowed for the establishment of normative ranges of serum testosterone levels on subcutaneous implant therapy. The study participants were 344 men who were accrued to an institutional review board-approved cohort study between April 2014 and 2017. Efficacy of the subcutaneous combination implant in maintaining low estradiol levels was evaluated. Serum levels of testosterone and estradiol were measured throughout the implant cycle, at week 4, and when symptoms returned. Correlations between patient demographics, dosing, and serum levels on therapy were evaluated. Mean testosterone dose was 1827 ± 262 mg. Mean anastrozole dose was 15.3 ± 3.2 mg with the majority of men receiving 16 mg of subcutaneous anastrozole. The mean interval of insertion was 4.8 months. Low estradiol levels were maintained throughout the implant cycle. Mean T level at week 4 was 1183 ± 315 ng/dl and 553 ± 239 ng/dl when symptoms returned. Levels of testosterone on therapy inversely correlated with body mass index. There were no adverse events attributed to testosterone or anastrozole therapy. Subcutaneous anastrozole delivered simultaneously with testosterone allowed for higher dosing of testosterone and less frequent intervals of insertion. Low-dose anastrozole released from the combination implant maintained low estradiol levels throughout the implant cycle and prevented clinical side effects attributed to excess estrogen.


Assuntos
Anastrozol , Inibidores da Aromatase/farmacologia , Estradiol/química , Testosterona , Anastrozol/uso terapêutico , Estudos de Coortes , Humanos , Masculino , Testosterona/uso terapêutico , Triazóis/química
12.
Poult Sci ; 98(11): 6100-6107, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31222318

RESUMO

An excessive amount of aromatase enzyme reduces reproductive performance in aging roosters. Testosterone metabolism by aromatase enzyme is one of the reasons for reduced testosterone and lower fertility of aging roosters. The purpose of this study was to determine the effects of Exemestane (EX), as a steroidal aromatase inhibitor, on the seminal parameters and reproductive hormones of aging roosters. A total of 20 roosters (45 wk of age) were housed in individual cages and received a standard basal diet and oral EX capsules for 60 D at the daily doses per rooster (mg/rooster) in the following experimental groups: 0 mg (CTRL), 0.25 mg (Ex-0.25), 0.5 mg (Ex-0.5), and 1.5 mg (Ex-1.5). Sperm samples were obtained on days 1, 20, 40, and 60 of experiment. Blood samples were taken on days 1 and 60. The results indicated that different EX dosages affected semen parameters (P < 0.05) other than semen volume, morphology, apoptosis, and acrosome integrity. Various semen characteristics were significant (P < 0.05) during different times of the experiment, with the exception of semen volume, total motility, membrane integrity, morphology, apoptosis, and acrosome integrity. Roosters that received 0.5 mg of EX had higher percentages of sperm concentration, total motility, progressive motility, membrane integrity, viability, and mitochondrial activity (P < 0.05). There were lower concentrations of malondialdehyde in the CTRL (0 mg) and Ex-0.25 groups (P < 0.05). Although there was no significant difference in hormones at day 0 of the experiment (P > 0.05), roosters in the Ex-0.5 had higher concentration of testosterone as well as lower of aromatase activity at day 60 (P < 0.05). It can be concluded that EX improved semen parameters and testosterone, which ultimately can increase fertility in the aging broiler breeder roosters.


Assuntos
Androstadienos/farmacologia , Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Galinhas/fisiologia , Sêmen/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Proteínas Aviárias/metabolismo , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Masculino , Sêmen/fisiologia , Análise do Sêmen/veterinária , Testículo/fisiologia , Testosterona/sangue
13.
Curr Top Med Chem ; 19(15): 1318-1337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31215379

RESUMO

Breast cancer is the most common cancer suffered by female, and the second highest cause of cancer-related death among women worldwide. At present, hormone therapy is still the main treatment route and can be divided into three main categories: selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). However, breast cancer is difficult to cure even after several rounds of anti-estrogen therapy and most drugs have serious side-effects. Here, we review the literature published over the past five years regarding the isolation and synthesis of analogs and their derivatives.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Antagonistas do Receptor de Estrogênio/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Inibidores da Aromatase/química , Inibidores da Aromatase/isolamento & purificação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Receptor de Estrogênio/química , Antagonistas do Receptor de Estrogênio/isolamento & purificação , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/isolamento & purificação , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Estrutura Molecular
14.
Theriogenology ; 136: 60-65, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252323

RESUMO

Sertoli cells nourish developing sperm with the number of Sertoli cells being a major determinant of sperm production capacity in a male. The objectives of these studies were to numerically characterize the prepuberal populations of bovine Sertoli cells to determine the pattern of proliferation and to determine if the prepuberal population could be expanded by reducing endogenous testicular estrogens. Groups of Angus-Hereford crossbred bull calves were castrated at 0.25 mo (n = 6) and 1, 2, 3, 4, 5, or 6 mo of age (n = 8 per age). Testes were weighed and equatorial slices fixed. Sertoli cell density was determined following labeling of Sertoli cells with GATA-4 antibody in 30-µm thick sections. The number of Sertoli cells per testis increased linearly from 0.25 mo to 5 mo of age. Sertoli cell numbers appeared to plateau at 5 mo of age with luminal development present at that age. Only a single postnatal wave of Sertoli cell proliferation was detectable in the bull. To evaluate the regulatory role of testicular estrogens, Jersey bull caves were treated twice weekly with the aromatase inhibitor, letrozole, from 2 to 22 wk of age and control animals were treated with the canola oil vehicle. Testes were retrieved at 26 wk of age. Testes were weighed and Sertoli cell density was subsequently determined. Estradiol was lower in testicular tissue from letrozole-treated bulls as expected (P < 0.001). Inhibition of aromatase had no effect on testosterone or circulating LH; testosterone increased with age as expected. Inhibition of aromatase and consequent reduced testicular estradiol did not alter Sertoli cell numbers.


Assuntos
Proliferação de Células/efeitos dos fármacos , Estradiol/metabolismo , Letrozol/farmacologia , Células de Sertoli/fisiologia , Maturidade Sexual/fisiologia , Testículo/efeitos dos fármacos , Envelhecimento , Animais , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/farmacologia , Bovinos , Letrozol/administração & dosagem , Masculino , Testículo/fisiologia
15.
J Steroid Biochem Mol Biol ; 193: 105411, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31207361

RESUMO

Reductive 17ß-hydroxysteroid dehydrogenases (17ß-HSDs) and 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) play crucial roles in respectively regulating steroids and glucocorticoids for the progression of hormone-dependent breast cancer. Most studies focused on the function and individual regulation of these enzymes. However, mutual regulation of these enzymes and the induced modulation on the estrogen and androgen receptors for breast cancer promotion are not yet clear. In this study, MCF-7 and T47D cells were treated with inhibitors of 17ß-HSD1, 17ß-HSD7, aromatase or steroid sulfatase (STS), then mRNA levels of 17ß-HSD7, STS, 11ß-HSD 2, estrogen receptors α (ERα) and androgen receptor (AR) were determined by Q-PCR. ER negative cell line MDA-MB-231 was used as a negative control. Our results demonstrate that 17ß-HSD7, STS and 11ß-HSD2 are all regulated by the same estrogen estradiol via ERα. When the gene of ERα (ESR1) was knocked down, there was no longer significant mutual regulation of these enzymes. Our results demonstrate that important steroidogenic enzymes transcriptionally regulated by ERα, can be mutually closely correlated. Inhibition of one of them can reduce the expression of another, thereby amplifying the role of the inhibition. Furthermore, inhibition of 17ß-HSD7 increases the expression of AR gene which is considered as a marker for better prognosis in ER + breast cancer, while maintaining ERα level. Thus, our mechanistic finding provides a base for further improving the endocrine therapy of ER + breast cancer, e.g., for selecting the target steroid enzymes, and for the combined targeting of human 17ß-HSD7 and ERα.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Receptores Androgênicos/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/genética , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Di-Hidrotestosterona/metabolismo , Estradiol/metabolismo , Feminino , Humanos , Esteril-Sulfatase/antagonistas & inibidores , Esteril-Sulfatase/genética , Esteril-Sulfatase/metabolismo
16.
Nat Commun ; 10(1): 2115, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073170

RESUMO

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/patologia , Citoesqueleto/patologia , Queratinas Tipo II/genética , Recidiva Local de Neoplasia/patologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Citoesqueleto/genética , Resistencia a Medicamentos Antineoplásicos/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Queratinas Tipo II/metabolismo , Células MCF-7 , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Domínios Proteicos/genética , Regulação para Cima
17.
Neurosci Lett ; 706: 61-67, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31077740

RESUMO

Estrogens (E2) derived from ovaries and/or local de novo synthesis in the hippocampus profoundly regulate hippocampal structure and function, but the importance of local E2 versus ovarian E2 on hippocampal synaptic plasticity and spatial memory has not been well elucidated. The present study used ovariectomy (OVX) and intraperitoneal injection of an E2 synthase inhibitor, letrozole (LET), in adult female mice to investigate changes in hippocampal steroid receptor coactivator-1 (SRC-1), postsynaptic proteins, and actin polymerization dynamics with these treatments. Changes in the CA1 spine density, synapse density and spatial learning and memory after OVX and LET were also investigated. As a result, OVX and LET showed similar regulation of the expression of GluR1, spinophilin and p-Cofilin, but LET tended to induce more significant changes in SRC-1, PSD95, Rictor, Cofilin and actin depolymerization. More significant decreases in F-actin/G-actin, CA1 spine density and synapse density were also observed after LET than after OVX. Notably, LET-treated mice showed worse learning and memory impairment than OVX mice. Taken together, these results demonstrated that circulating E2 played a limited role and that hippocampus-derived E2 played a more important role in the regulation of hippocampal synaptic plasticity and hippocampus-based spatial learning and memory.


Assuntos
Inibidores da Aromatase/farmacologia , Dendritos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Letrozol/farmacologia , Memória Espacial/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Actinas/metabolismo , Animais , Dendritos/metabolismo , Feminino , Hipocampo/metabolismo , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Ovariectomia , Aprendizagem Espacial/efeitos dos fármacos , Sinapses/metabolismo
18.
Eur J Med Chem ; 177: 116-143, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129450

RESUMO

Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a powerful predictive and prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with various estrogen ligands. ER consists of two subtypes i.e. ERα and ERß, that are mostly G-protein-coupled receptors and activated by estrogen, specially 17ß-estradiol. The activation is followed by translocation into the nucleus and binding with DNA to modulate activities of different genes. ERs can manage synthesis of RNA through genomic actions without directly binding to DNA. Receptors are tethered by protein-protein interactions to a transcription factor complex to communicate with DNA. Estrogens also exhibit nongenomic actions, a characteristic feature of steroid hormones, which are so rapid to be considered by the activation of RNA and translation. These are habitually related to stimulation of different protein kinase cascades. Majority of post-menopausal breast cancer is estrogen dependent, mostly potent biological estrogen (E2) for continuous growth and proliferation. Estrogen helps in regulating the differentiation and proliferation of normal breast epithelial cells. In this review we have investigated the important role of ER in development and progression of breast cancer, which is complicated by receptor's interaction with co-regulatory proteins, cross-talk with other signal transduction pathways and development of treatment strategies viz. selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs), aromatase and sulphatase inhibitors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/uso terapêutico , Receptores Estrogênicos/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Linhagem Celular Tumoral , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacologia , Estrogênios/química , Estrogênios/farmacologia , Feminino , Humanos , Ligantes , Homens , Estrutura Molecular , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transdução de Sinais/fisiologia , Sulfatases/antagonistas & inibidores
19.
Molecules ; 24(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072017

RESUMO

Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10ß-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10ß-fluoroestra-1,4-dien-3-one and 10ß-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with trans ring anellations and a 13ß-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13ß-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC50 values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.


Assuntos
Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Estrona/síntese química , Estrona/farmacologia , Simulação de Acoplamento Molecular , Inibidores da Aromatase/química , Estrona/química , Halogenação , Humanos , Ligantes , Padrões de Referência
20.
Gen Comp Endocrinol ; 281: 17-29, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085192

RESUMO

Previous studies revealed an estradiol (E2)-dependent peak in brain activity, including neurosteroidogenesis and neurogenesis in the black porgy during the gonadal differentiation period. The brain-pituitary-gonadotropic axis is a key regulator of reproduction and may also be involved in gonadal differentiation, but its activity and potential role in black porgy during the gonadal differentiation period is still unknown. The present study analyzed the expression of regulatory factors involved in the gonadotropic axis at the time of gonadal differentiation (90, 120, 150 days after hatching [dah]) and subsequent testicular development (180, 210, 300 dah). In agreement with previous studies, expression of brain aromatase cyp19a1b peaked at 120 dah, and this was followed by a gradual increase during testicular development. The expression of gonadotropin subunits increased slightly but not significantly during gonadal differentiation and then increased significantly at 300 dah. In contrast, the expression of brain gnrh1 and pituitary gnrh receptor 1 (gnrhr1) exhibited a pattern with two peaks, the first at 120 dah, during the period of gonadal differentiation, and the second peak during testicular development. Gonad fshr and lhcgr increased during gonadal differentiation period with highest transcript level in prespawning season during testicular development. This suggests that the early activation of brain gnrh1, pituitary gnrhr1 and gths, and gonad gthrs might be involved in the control of gonadal differentiation. E2 treatment increased brain cyp19a1b expression at each sampling time, in agreement with previous studies in black porgy and other teleosts. E2 also significantly stimulated the expression of pituitary gonadotropin subunits at all sampling times, indicating potential E2-mediated steroid feedback. In contrast, no significant effect of E2 was observed on gnrh1. Moreover, treatment of AI or E2 had no statistically significant effect on brain gnrh1 transcription levels during gonadal differentiation. This indicated that the early peak of gnrh1 expression during the gonadal differentiation period is E2-independent and therefore not directly related to the E2-dependent peak in brain neurosteroidogenesis and neurogenesis also occurring during this period in black porgy. Both E2-independent and E2-dependent mechanisms are thus involved in the peak expression of various genes in the brain of black porgy at the time of gonadal differentiation.


Assuntos
Encéfalo/metabolismo , Estradiol/farmacologia , Perciformes/fisiologia , Hipófise/metabolismo , Diferenciação Sexual , Testículo/crescimento & desenvolvimento , Animais , Aromatase/genética , Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gonadotropinas Hipofisárias/genética , Gonadotropinas Hipofisárias/metabolismo , Masculino , Perciformes/genética , Perciformes/crescimento & desenvolvimento , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores LHRH/genética , Receptores LHRH/metabolismo , Diferenciação Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo
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