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1.
Mol Pharmacol ; 98(1): 24-37, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32362585

RESUMO

High-dose synthetic estrogen therapy was the standard treatment of advanced breast cancer for three decades until the discovery of tamoxifen. A range of substituted triphenylethylene synthetic estrogens and diethylstilbestrol were used. It is now known that low doses of estrogens can cause apoptosis in long-term estrogen deprived (LTED) breast cancer cells resistant to antiestrogens. This action of estrogen can explain the reduced breast cancer incidence in postmenopausal women over 60 who are taking conjugated equine estrogens and the beneficial effect of low-dose estrogen treatment of patients with acquired aromatase inhibitor resistance in clinical trials. To decipher the molecular mechanism of estrogens at the estrogen receptor (ER) complex by different types of estrogens-planar [17ß-estradiol (E2)] and angular triphenylethylene (TPE) derivatives-we have synthesized a small series of compounds with either no substitutions on the TPE phenyl ring containing the antiestrogenic side chain of endoxifen or a free hydroxyl. In the first week of treatment with E2 the LTED cells undergo apoptosis completely. By contrast, the test TPE derivatives act as antiestrogens with a free para-hydroxyl on the phenyl ring that contains an antiestrogenic side chain in endoxifen. This inhibits early E2-induced apoptosis if a free hydroxyl is present. No substitution at the site occupied by the antiestrogenic side chain of endoxifen results in early apoptosis similar to planar E2 The TPE compounds recruit coregulators to the ER differentially and predictably, leading to delayed apoptosis in these cells. SIGNIFICANCE STATEMENT: In this paper we investigate the role of the structure-function relationship of a panel of synthetic triphenylethylene (TPE) derivatives and a novel mechanism of estrogen-induced cell death in breast cancer, which is now clinically relevant. Our study indicates that these TPE derivatives, depending on the positioning of the hydroxyl groups, induce various conformations of the estrogen receptor's ligand-binding domain, which in turn produces differential recruitment of coregulators and subsequently different apoptotic effects on the antiestrogen-resistant breast cancer cells.


Assuntos
Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios/síntese química , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Estilbenos/síntese química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estradiol/química , Estradiol/farmacologia , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Estilbenos/química , Estilbenos/farmacologia , Relação Estrutura-Atividade
3.
Toxicol Lett ; 319: 22-30, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689473

RESUMO

Cadmium (Cd) has estrogen-like activities in breast cancer; it acts as a metalloestrogen in humans. Prospective cohort studies of Cd and breast cancer risk suggest a significant relationship between increased Cd intake and cancer incidence, with more pronounced effects for estrogen receptor α (ERα)-positive breast cancers. However, a recent systematic review with the highest level of evidence demonstrated no such relationship in post-menopausal women. Thus, the reported effects of Cd in pre- and post-menopausal ERα-positive breast cancers are inconsistent. MCF-7 human breast cancer cells normally exhibit growth through estradiol-triggered ERα signaling; however, the MCF-7 cells cultured in estrogen-deprived conditions for a long time (∼ 6 months) eventually result in LTED cells that can be used to utilize to study the proliferation of ERα-positive breast cancer cells obtained from post-menopausal women. Our results showed that unlike MCF-7 cells, LTED cells showed estradiol-independent growth because of constitutively activated ERα. Moreover, Cd (∼10 nM) stimulated ERα signaling in MCF-7 cells and ERα-expressing LTED cells, but not in LTED cells; in ERα-expressing LTED cells, this effect was reversed by ICI 182,780 (an ERα antagonist). Furthermore, in comparison with MCF-7 cells, the LTED cells expressed very low levels of G protein-coupled estrogen receptor 1 (GPER1), a membrane ER capable of stimulating the estrogenic activity of Cd. These findings suggest that the estrogenic action of Cd may be suppressed in LTED cells, and potentially in post-menopausal breast cancer.


Assuntos
Cloreto de Cádmio/toxicidade , Receptor alfa de Estrogênio/metabolismo , Estrogênios/biossíntese , Estrogênios/deficiência , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7
4.
Nat Commun ; 10(1): 5745, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848339

RESUMO

Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.


Assuntos
Estrogênios/metabolismo , Neoplasias Hepáticas/secundário , Fígado/patologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral/transplante , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Estradiol/administração & dosagem , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/imunologia , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Ovariectomia , Neoplasias Pancreáticas/patologia , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Fatores Sexuais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
5.
Molecules ; 24(21)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683895

RESUMO

Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ERα modulators (4 and 5) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative 5a showed the highest binding affinity toward ERα because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative 5d maintained high binding affinity to ERα and potently inhibited MCF-7 cell proliferation (IC50: 0.09 µM). Docking simulation studies of compound 5d with the ERα BD revealed that the large hydrophobic moiety of compound 5d fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound 5d formed a sulfur-π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound 5d to the ERα LBD.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Antagonistas de Estrogênios/síntese química , Moduladores de Receptor Estrogênico/síntese química , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Células MCF-7 , Relação Estrutura-Atividade , Enxofre/química
6.
Mutat Res ; 845: 402993, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31561897

RESUMO

Phenolic groups of steroidal or nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17ß-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 µM (P < 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P < 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells' antioxidant capacity.


Assuntos
Antioxidantes/farmacologia , Células Sanguíneas/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dietilestilbestrol/antagonistas & inibidores , Estradiol/toxicidade , Antagonistas de Estrogênios/farmacologia , Depuradores de Radicais Livres/farmacologia , Olea/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Adulto , Ensaio Cometa , Dietilestilbestrol/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Oxirredução , Estresse Oxidativo , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio , Adulto Jovem
7.
J Mol Model ; 25(9): 278, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31463793

RESUMO

Estrogen receptor (ER) is a nuclear hormone receptor and plays an important role in mediating the cellular effects of estrogen. ER can be classified into two receptors: estrogen receptor alpha (ERα) and beta (ERß), and the former is expressed in 50~80% of breast tumors and has been extensively investigated in breast cancer for decades. Excessive exposure to estrogen can obviously stimulate the growth of breast cancers primarily mediated by ERα, and thus anti-estrogen therapies by small molecules are of concern to clinicians and pharmaceutical industry in the treatment of ERα-positive breast cancers. Although a series of estrogen receptor modulators have been developed, these drugs can lead to resistance and side effects. Therefore, the development of small molecule inhibitors with high target specificity has been intensified. In this pursuit, an integrated computer-aided virtual screening technique, including molecular docking and pharmacophore model screening, was used to screen traditional Chinese medicine (TCM) databases. The compounds with high docking scores and fit values were subjected to ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction, and ten hits were identified as potential inhibitors targeting ERα. Molecular docking was used to investigate the binding modes between ERα and three most potent hits, and molecular dynamic simulations were chosen to explore the stability of these complexes. The rank of the predicted binding free energies evaluated by MM/GBSA is consistent with the docking score. These novel scaffolds discovered in the present study can be used as critical starting point in the drug discovery process for treating ERα-positive breast cancer. Graphical abstract .


Assuntos
Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Estrogênios/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Medicina Tradicional Chinesa , Conformação Proteica , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico
8.
Eur J Med Chem ; 182: 111605, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437778

RESUMO

Hormone therapy is widely used in clinic for breast cancer treatment, such as tamoxifen, but long-term use can cause drug resistance. In this regard, a strategy based on small molecule-induced protein degradation, i.e. selective estrogen receptor downregulator (SERD), might be an effective alternative to hormone therapy for breast cancer. However, most of the SERD candidates involve very limited scaffolds and are still in clinical trials, and none of them has been approved for marketing. In this study, a series of novel 7-oxabicyclo[2.2.1]heptene sulfonamide (OBHSA) derivatives with long alkyl chains were identified as novel SERDs. We found that the position and the length of alkyl side chain have significant effect on the biological activity of the SERD compounds and with the six-carbon side chain was the best. Among them, compounds 23a and 36 displayed potent inhibitory activity against MCF-7 breast cancer cell line with IC50 values of 0.84 µM and 0.77 µM, respectively, as well as excellent ERα degradation activity. Primary mechanism study indicated that the degradation of ERα is mediated through proteasome-mediated process. Flow cytometry analysis of apoptosis of 36 suggested that the effect of this type compounds on MCF-7 cells is associated with apoptosis. As such, these compounds have shown potential to become promising leads for the development of highly efficient SERDs for drug-resistance breast cancer therapies.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/química , Receptor alfa de Estrogênio/metabolismo , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas
9.
Toxicology ; 426: 152256, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31381935

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in substantia nigra (SN). Accumulating evidences implicate the beneficial role of estrogen in the therapy of PD. METHODS: In the present study, the protective function of luteolin-7-O-glucoside (LUT-7G), a natural flavonoid, was investigated in 1-methyl-4-phenylpyridinium (MPP+) treated SH-SY5Y cells and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced mice. RESULTS: Pre-treatment of LUT-7G increased the viability and reduced the apoptosis of SH-SY5Y cells treated by MPP+. At molecular level, the Bcl-2/Bax ratio was increased, while the expression of cleaved caspase 3 was markedly lessened. Moreover, LUT-7G increased the expression of estrogen receptor (ER), ERα and ERß, and enhanced the activation of ERK1/2/STAT3/c-Fos that could be abolished by ER antagonists. Furthermore, in vivo experiment indicated that pre-treatment of LUT-7G improved the bradykinesia, and enhanced the muscle strength as well as the balancing capacity of mice treated with MPTP. And LUT-7G prevented the injury of TH positive cells in substantia nigra and increased TH positive nerve fibers in striatum. In addition, pre-treatment of LUT-7G also significantly diminished the MPTP-induced gliosis in substantia nigra. CONCLUSIONS: LUT-7G effectively protected dopaminergic neurons against MPP+ or MPTP-induced toxicity, probably by activating the ER-mediated signaling pathway. Our findings explore the therapeutic potential of LUT-7G for PD therapy.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Flavonas/farmacologia , Glucosídeos/farmacologia , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Receptores Estrogênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Antagonistas de Estrogênios/farmacologia , Humanos , Hipocinesia/etiologia , Hipocinesia/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Intoxicação por MPTP/patologia , Intoxicação por MPTP/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular/efeitos dos fármacos , Fator de Transcrição STAT3/efeitos dos fármacos , Substância Negra/patologia
10.
Oncogene ; 38(43): 6913-6925, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31406251

RESUMO

Metastatic, antiestrogen resistant estrogen receptor α positive (ER+) breast cancer is the leading cause of breast cancer deaths in USA women. While studies have demonstrated the importance of the stromal tumor microenvironment in cancer progression and therapeutic responses, effects on the responses of ER+ cancers to estrogen and antiestrogens are poorly understood, particularly in the complex in vivo environment. In this study, we used an estrogen responsive syngeneic mouse model to interrogate how a COL1A1-enriched fibrotic ECM modulates integrated hormonal responses in cancer progression. We orthotopically transplanted the ER+ TC11 cell line into wild-type (WT) or collagen-dense (Col1a1tm1Jae/+, mCol1a1) syngeneic FVB/N female mice. Once tumors were established, recipients were supplemented with 17ß-estradiol (E2), tamoxifen, or left untreated. Although the dense/stiff environment in mCol1a1 recipients did not alter the rate of E2-induced proliferation of the primary tumor, it fostered the agonist activity of tamoxifen to increase proliferation and AP-1 activity. Manipulation of estrogen activity did not alter the incidence of lung lesions in either WT or mCol1a1 hosts. However, the mCol1a1 environment enabled tamoxifen-stimulated growth of pulmonary metastases and further fueled estrogen-driven growth. Moreover, E2 remodeled peritumoral ECM architecture in WT animals, modifying alignment of collagen fibers and altering synthesis of ECM components associated with increased alignment and stiffness, and increasing FN1 and POSTN expression in the pulmonary metastatic niche. These studies demonstrate dynamic interactions between ECM properties and estrogen activity in progression of ER+ breast cancer, and support the need for therapeutics that target both ER and the tumor microenvironment.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Matriz Extracelular/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Estradiol/metabolismo , Antagonistas de Estrogênios/farmacologia , Matriz Extracelular/efeitos dos fármacos , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Tamoxifeno/farmacologia , Microambiente Tumoral/efeitos dos fármacos
11.
Am J Physiol Renal Physiol ; 317(5): F1154-F1163, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461351

RESUMO

Tachykinins (TKs) are involved in both the physiological regulation of urinary bladder functions and development of overactive bladder syndrome. The aim of the present study was to investigate the signal transduction pathways of TKs in the detrusor muscle to provide potential pharmacological targets for the treatment of bladder dysfunctions related to enhanced TK production. Contraction force, intracellular Ca2+ concentration, and RhoA activity were measured in the mouse urinary bladder smooth muscle (UBSM). TKs and the NK2 receptor (NK2R)-specific agonist [ß-Ala8]-NKA(4-10) evoked contraction, which was inhibited by the NKR2 antagonist MEN10376. In Gαq/11-deficient mice, [ß-Ala8]-NKA(4-10)-induced contraction and the intracellular Ca2+ concentration increase were abolished. Although Gq/11 proteins are linked principally to phospholipase Cß and inositol trisphosphate-mediated Ca2+ release from intracellular stores, we found that phospholipase Cß inhibition and sarcoplasmic reticulum Ca2+ depletion failed to have any effect on contraction induced by [ß-Ala8]-NKA(4-10). In contrast, lack of extracellular Ca2+ or blockade of voltage-dependent Ca2+ channels (VDCCs) suppressed contraction. Furthermore, [ß-Ala8]-NKA(4-10) increased RhoA activity in the UBSM in a Gq/11-dependent manner and inhibition of Rho kinase with Y-27632 decreased contraction force, whereas the combination of Y-27632 with either VDCC blockade or depletion of extracellular Ca2+ resulted in complete inhibition of [ß-Ala8]-NKA(4-10)-induced contractions. In summary, our results indicate that NK2Rs are linked exclusively to Gq/11 proteins in the UBSM and that the intracellular signaling involves the simultaneous activation of VDCC and the RhoA-Rho kinase pathway. These findings may help to identify potential therapeutic targets of bladder dysfunctions related to upregulation of TKs.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Músculo Liso/fisiologia , Receptores da Neurocinina-2/fisiologia , Bexiga Urinária/fisiologia , Quinases Associadas a rho/metabolismo , Animais , Cálcio/metabolismo , Antagonistas de Estrogênios/farmacologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Contração Muscular/efeitos dos fármacos , Taquicininas/metabolismo , Tamoxifeno/farmacologia , Quinases Associadas a rho/genética
12.
Health Psychol ; 38(10): 888-899, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31343218

RESUMO

OBJECTIVE: Previous research has shown that up to 50% of breast cancer survivors prescribed tamoxifen do not take it as recommended, which is associated with increased risk of recurrence and mortality. Little research has attempted to identify modifiable psychosocial factors associated with tamoxifen nonadherence. This study aimed to examine how tamoxifen adherence rates change over a year and to identify modifiable predictors of nonadherence. METHOD: Three hundred and forty-five breast cancer survivors who were in their first year of tamoxifen prescription were sent questionnaires at 4 points over a 12-month period. Questionnaires assessed demographic and clinical factors, side effects, beliefs about the illness and medication, social support, distress and tamoxifen adherence. Adherence was assessed using the Medication Adherence Rating Scale. Latent Growth Modeling was used to identify predictors of tamoxifen nonadherence. RESULTS: Reported rates of nonadherence increased over time (37-48%). Several demographic, clinical, and psychosocial variables were associated with nonadherence. Women who were nonadherent were more likely to be from a minority ethnic group, to have more negative medication beliefs and to have lower confidence in their ability to take tamoxifen. CONCLUSIONS: These demographic and clinical variables can be used to identify women at higher risk of nonadherence. The modifiable psychosocial variables can be used as the basis for psychological interventions to improve adherence in this population. Interventions should focus on both intentional and unintentional nonadherence. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Neoplasias da Mama/psicologia , Antagonistas de Estrogênios/uso terapêutico , Adesão à Medicação/psicologia , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Sobreviventes de Câncer , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Tamoxifeno/farmacologia , Fatores de Tempo
13.
J Steroid Biochem Mol Biol ; 193: 105415, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31226312

RESUMO

Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17ß. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of immune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been effective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are unresponsive to current endocrine therapies.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Antagonistas de Estrogênios/farmacologia , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores Estrogênicos/metabolismo
14.
Mycoses ; 62(9): 818-825, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31173410

RESUMO

BACKGROUND: Cryptococcal meningitis has fatality rates of 40%-70%, resulting in 200 000 deaths each year. The best outcomes are achieved with amphotericin combined with flucytosine but flucytosine is expensive and unavailable where most disease occurs. More effective and affordable treatments are needed. Tamoxifen, a selective oestrogen receptor modulator frequently indicated for breast cancer, has been found to have synergistic activity against the Cryptococcus neoformans type strain when combined with amphotericin or fluconazole. It is cheap, off-licence, widely available and well-tolerated, and thus a pragmatic potential treatment for cryptococcal disease. OBJECTIVES: We wanted to determine the susceptibility of clinical isolates of C. neoformans to tamoxifen alone and in combination with other antifungals, to determine whether there is sufficient evidence of activity to justify a clinical trial. METHODS: We used the CLSI broth microdilution protocol to test the susceptibility of 30 randomly selected clinical isolates of C. neoformans to tamoxifen, in dual combination with amphotericin, fluconazole or flucytosine, and in triple combination with amphotericin and fluconazole. Evidence of drug interactions was assessed using the fractional inhibitory concentration index. RESULTS: The MIC50 and MIC90 of tamoxifen were 4 and 16 mg/L, respectively. The combination of tamoxifen and amphotericin suggested a synergistic interaction in 20 of 30 (67%) isolates. There was no interaction between tamoxifen and either fluconazole or flucytosine. Synergy was maintained in 3-Dimensional chequerboard testing. There was no evidence of antagonism. CONCLUSIONS: Tamoxifen may be a useful addition to treatment with amphotericin and fluconazole for cryptococcal meningitis; a trial is justified.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Fluconazol/farmacologia , Tamoxifeno/farmacologia , Cryptococcus neoformans/isolamento & purificação , Sinergismo Farmacológico , Humanos , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/microbiologia , Testes de Sensibilidade Microbiana
15.
Mol Oncol ; 13(7): 1534-1547, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31099456

RESUMO

Estrogens play a pivotal role in breast cancer etiology, and endocrine therapy remains the main first line treatment for estrogen receptor-alpha (ERα)-positive breast cancer. ER are transcription factors whose activity is finely regulated by various regulatory complexes, including histone deacetylases (HDACs). Here, we investigated the role of HDAC9 in ERα signaling and response to antiestrogens in breast cancer cells. Various Michigan Cancer Foundation-7 (MCF7) breast cancer cell lines that overexpress class IIa HDAC9 or that are resistant to the partial antiestrogen 4-hydroxy-tamoxifen (OHTam) were used to study phenotypic changes in response to ER ligands by using transcriptomic and gene set enrichment analyses. Kaplan-Meier survival analyses were performed using public transcriptomic datasets from human breast cancer biopsies. In MCF7 breast cancer cells, HDAC9 decreased ERα mRNA and protein expression and inhibited its transcriptional activity. Conversely, HDAC9 mRNA was strongly overexpressed in OHTam-resistant MCF7 cells and in ERα-negative breast tumor cell lines. Moreover, HDAC9-overexpressing cells were less sensitive to OHTam antiproliferative effects compared with parental MCF7 cells. Several genes (including MUC1, SMC3 and S100P) were similarly deregulated in OHTam-resistant and in HDAC9-overexpressing MCF7 cells. Finally, HDAC9 expression was positively associated with genes upregulated in endocrine therapy-resistant breast cancers and high HDAC9 levels were associated with worse prognosis in patients treated with OHTam. These results demonstrate the complex interactions of class IIa HDAC9 with ERα signaling in breast cancer cells and its effect on the response to hormone therapy.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Antagonistas de Estrogênios/farmacologia , Histona Desacetilases/genética , Proteínas Repressoras/genética , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
16.
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
17.
Bioorg Med Chem ; 27(10): 1952-1961, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940565

RESUMO

Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.


Assuntos
Compostos Benzidrílicos/química , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/antagonistas & inibidores , Compostos Benzidrílicos/farmacologia , Sítios de Ligação , Ciclofenil/química , Ciclofenil/metabolismo , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Fenóis/química , Fenóis/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
18.
Oxid Med Cell Longev ; 2019: 7670854, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728891

RESUMO

Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 µmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91 phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin's inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.


Assuntos
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Antagonistas de Estrogênios/uso terapêutico , Flavanonas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Antagonistas de Estrogênios/farmacologia , Flavanonas/farmacologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Transfecção
19.
J Neurochem ; 150(2): 173-187, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30790293

RESUMO

Clinical and animal studies have revealed sex-specific differences in histopathological and neurological outcome after traumatic brain injury (TBI). The impact of perioperative administration of sex steroid inhibitors on TBI is still elusive. Here, we subjected male and female C57Bl/6N mice to the controlled cortical impact (CCI) model of TBI and applied pharmacological inhibitors of steroid hormone synthesis, that is, letrozole (LET, inhibiting estradiol synthesis by aromatase) and finasteride (FIN, inhibiting dihydrotestosterone synthesis by 5α-reductase), respectively, starting 72 h prior CCI, and continuing for a further 48 h after CCI. Initial gene expression analyses showed that androgen (Ar) and estrogen receptors (Esr1) were sex-specifically altered 72 h after CCI. When examining brain lesion size, we found larger lesions in male than in female mice, but did not observe effects of FIN or LET treatment. However, LET treatment exacerbated neurological deficits 24 and 72 h after CCI. On the molecular level, FIN administration reduced calpain-dependent spectrin breakdown products, a proxy of excitotoxicity and disturbed Ca2+ homeostasis, specifically in males, whereas LET increased the reactive astrocyte marker glial fibrillary acid protein specifically in females. Examination of neurotrophins (brain-derived neurotrophic factor, neuronal growth factor, NT-3) and their receptors (p75NTR , TrkA, TrkB, TrkC) revealed CCI-induced down-regulation of TrkB and TrkC protein expression, which was reduced by LET in both sexes. Interestingly, FIN decreased neuronal growth factor mRNA expression and protein levels of its receptor TrkA only in males. Taken together, our data suggest a sex-specific impact on pathogenic processes in the injured brain after TBI. Sex hormones may thus modulate pathogenic processes in experimental TBI.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Encéfalo/efeitos dos fármacos , Di-Hidrotestosterona/antagonistas & inibidores , Estradiol/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Antagonistas de Estrogênios/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/efeitos dos fármacos , Caracteres Sexuais
20.
Phytother Res ; 33(4): 1114-1121, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30768735

RESUMO

Two kinds of microglia are known, classical M1 and alternative M2 phenotypes. Amyloid ß (Aß), a critical cause of Alzheimer's disease (AD), promotes M1 microglial polarization, leading to neuroinflammation and neuronal death. M2 microglia play important roles in anti-inflammatory effects, Aß clearance, and memory recovery in AD. Therefore, increasing of M2 microglia is expected to recover from AD. We previously found that naringenin, a blood-brain barrier penetrating compound, decreased Aß deposits and recovers memory function in transgenic AD model mice. Naringenin reportedly showed anti-inflammatory properties. Here, we aim to investigate potential effects of naringenin on microglial polarization and to reveal the underlying mechanisms of Aß reduction. Primary cultured cortical microglia were treated with Aß1-42 , following administration of naringenin. Naringenin remarkably promoted M2 microglia polarization and inhibited Aß1-42 -induced M1 microglia activation. Because microglia reportedly played a critical role in cerebral Aß clearance through Aß degradation enzymes after phagocytosis, we investigated the expression of Aß degradation enzymes, such as neprilysin and insulin degradation enzyme. After naringenin treatment, these Aß degradation enzymes were downregulated in M1 microglia and upregulated in M2 microglia. Taken together, our results showed that naringenin increased Aß degradation enzymes in M2 microglia, probably leading to Aß plaque reduction.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Antagonistas de Estrogênios/uso terapêutico , Flavanonas/química , Microglia/efeitos dos fármacos , Animais , Antagonistas de Estrogênios/farmacologia , Masculino , Camundongos , Camundongos Transgênicos
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