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1.
Int J Mol Sci ; 24(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36675194

RESUMO

Various literature data show how a diet rich in vegetables could reduce the incidence of several cancers due to the contribution of the natural polyphenols contained in them. Polyphenols are attributed multiple pharmacological actions such as anti-inflammatory, anti-oxidant, antibiotic, antiseptic, anti-allergic, cardioprotective and even anti-tumor properties. The multiple mechanisms involved in their anti-tumor action include signaling pathways modulation associated with cell proliferation, differentiation, migration, angiogenesis, metastasis and cell death. Since the dysregulation of death processes is involved in cancer etiopathology, the natural compounds able to kill cancer cells could be used as new anticancer agents. Apoptosis, a programmed form of cell death, is the most potent defense against cancer and the main mechanism used by both chemotherapy agents and polyphenols. The aim of this review is to provide an update of literature data on the apoptotic molecular mechanisms induced by some representative polyphenol family members in cancer cells. This aspect is particularly important because it may be useful in the design of new therapeutic strategies against cancer involving the polyphenols as adjuvants.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dieta , Apoptose , Antioxidantes/farmacologia
2.
Int J Mol Sci ; 24(12)2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37373242

RESUMO

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/metabolismo , Resveratrol/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Encefálicas/metabolismo , Transdução de Sinais , Células-Tronco Neoplásicas/metabolismo , Proliferação de Células
3.
Int J Mol Sci ; 23(11)2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35682974

RESUMO

Notch signaling dysregulation encourages breast cancer progression through different mechanisms such as stem cell maintenance, cell proliferation and migration/invasion. Furthermore, Notch is a crucial driver regulating juxtracrine and paracrine communications between tumor and stroma. The complex interplay between the abnormal Notch pathway orchestrating the activation of other signals and cellular heterogeneity contribute towards remodeling of the tumor microenvironment. These changes, together with tumor evolution and treatment pressure, drive breast cancer drug resistance. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance, reducing or eliminating breast cancer stem cells. In the present review, we will summarize the current scientific evidence that highlights the involvement of Notch activation within the breast tumor microenvironment, angiogenesis, extracellular matrix remodeling, and tumor/stroma/immune system interplay and its involvement in mechanisms of therapy resistance.


Assuntos
Neoplasias da Mama , Microambiente Tumoral , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Receptores Notch/metabolismo , Transdução de Sinais
4.
Int J Mol Sci ; 23(3)2022 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-35163166

RESUMO

It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα complex activates multiple pathways involved in both cell cycle progression and apoptotic cascade prevention, while E2/ERß complex in many cases directs the cells to apoptosis. However, the exact mechanism of estrogen-induced tumor regression is not completely known. Nevertheless, ERs expression levels of specific splice variants and their cellular localization differentially affect outcome of estrogen-dependent tumors. The goal of this review is to provide a general overview of current knowledge on ERs-mediated apoptosis that occurs in main hormone dependent-cancers. Understanding the molecular mechanisms underlying the induction of ER-mediated cell death will be useful for the development of specific ligands capable of triggering apoptosis to counteract estrogen-dependent tumor growth.


Assuntos
Apoptose , Neoplasias Hormônio-Dependentes/patologia , Receptores de Estrogênio/metabolismo , Animais , Humanos , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/metabolismo , Receptores de Estrogênio/genética , Transdução de Sinais
5.
J Cell Mol Med ; 25(8): 3856-3869, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33650791

RESUMO

Adrenocortical cancer (ACC) is a rare tumour with unfavourable prognosis, lacking an effective treatment. This tumour is characterized by IGF-II (insulin-like growth factor II) overproduction, aromatase and ERα (oestrogen receptor alpha) up-regulation. Previous reports suggest that ERα expression can be regulated by sirt1 (sirtuin 1), a nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylases that modulates activity of several substrates involved in cellular stress, metabolism, proliferation, senescence, protein degradation and apoptosis. Nevertheless, sirt1 can act as a tumour suppressor or oncogenic protein. In this study, we found that in H295R and SW13 cell lines, sirt1 expression is inhibited by sirtinol, a potent inhibitor of sirt1 activity. In addition, sirtinol is able to decrease ACC cell proliferation, colony and spheroids formation and to activate the intrinsic apoptotic mechanism. Particularly, we observed that sirtinol interferes with E2/ERα and IGF1R (insulin growth factor 1 receptor) pathways by decreasing receptors expression. Sirt1 involvement was confirmed by using a specific sirt1 siRNA. More importantly, we observed that sirtinol can synergize with mitotane, a selective adrenolitic drug, in inhibiting adrenocortical cancer cell growth. Collectively, our data reveal an oncogenic role for sirt1 in ACC and its targeting could implement treatment options for this type of cancer.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , RNA Interferente Pequeno/genética , Sirtuína 1/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Apoptose , Humanos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Células Tumorais Cultivadas
6.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067547

RESUMO

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Resveratrol/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Resveratrol/análogos & derivados
7.
Pharm Res ; 37(3): 55, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060727

RESUMO

PURPOSE: Solid tumors exhibit an altered redox state in comparison with normal tissues due to tumor hypoxia, lower pH, and elevated levels of the tripeptide glutathione. This study describes the preparation of functional redox-responsive nanoparticles proposed as delivery vehicle of Doxorubicin in adrenocortical cancer in vitro. METHODS: Curcumin and Lipoic acid were conjugated to Human Serum Albumin and nanoparticle systems were prepared via a modified desolvation method. Scanning electron microscopy, Fourier transmission IR, dynamic light scattering and differential scanning calorimetry analyses were used to characterize the nanoparticles. Balb3T3 and H295R were used as in vitro models of health and cancer cells, respectively. RESULTS: Nanoparticles with a spherical shape and a mean diameter of 70 nm were observed, increasing up to ten-folds upon exposure to glutathione 10 mM. Redox responsive Doxorubicin release was recorded, with loaded nanoparticles significantly enhancing the drug cytotoxicity against H295R adrenocortical tumor cells. Cell uptake experiments revealed a rapid and efficient internalization of the nanoparticles. CONCLUSIONS: A valuable tools to actively improve the in vitro anticancer activity of Doxorubicin against adrenocortical cancer was proposed. The effectiveness of the delivery vehicle is related to the presence of both Lipoic acid and Curcumin moieties, enhancing the glutathione responsivity, and the drug cytotoxicity, respectively.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Albuminas/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Humanos , Camundongos , Tamanho da Partícula , Ácido Tióctico
8.
Int J Mol Sci ; 20(5)2019 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832393

RESUMO

Extensive research over the past 25 years in hormone-dependent cancers, such as breast cancer and prostate cancer, has identified the molecular mechanisms driven by steroid receptors, elucidating the interplay between genomic and non-genomic steroid receptors mechanism of action. Altogether, these mechanisms create the specific gene expression programs that contribute to endocrine therapy resistance and cancer progression. These findings, on the bidirectional molecular crosstalk between steroid and growth factor receptors pathways in endocrine resistance, suggest the use of multi-target inhibitors together with endocrine therapies, for treating resistant disease. In this review we will discuss the novel understanding on the chemopreventive and anti-cancer activities of Resveratrol (3,5,4'-trihydroxy-stilbene) (RSV), a phytoalexin found in grapes acting on a plethora of targets. We will highlight Resveratrol effect on steroid receptors signalling and its potential use in the treatment of hormone-dependent cancer. Understanding the molecular mechanisms by which the bioactive compound influences cancer cell behaviour, by interfering with steroid receptors functional activity, will help to advance the design of combination strategies to increase the rate of complete and durable clinical response in patients.


Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Receptores de Esteroides/metabolismo , Resveratrol/farmacologia , Animais , Anticarcinógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Masculino , Neoplasias da Próstata/prevenção & controle , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
9.
Int J Mol Sci ; 20(6)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893846

RESUMO

Resveratrol (3,5,4'-trihydroxystilbene; RSV) is a natural nonflavonoid polyphenol present in many species of plants, particularly in grapes, blueberries, and peanuts. Several in vitro and in vivo studies have shown that in addition to antioxidant, anti-inflammatory, cardioprotective and neuroprotective actions, it exhibits antitumor properties. In mammalian models, RSV is extensively metabolized and rapidly eliminated and therefore it shows a poor bioavailability, in spite it of its lipophilic nature. During the past decade, in order to improve RSV low aqueous solubility, absorption, membrane transport, and its poor bioavailability, various methodological approaches and different synthetic derivatives have been developed. In this review, we will describe the strategies used to improve pharmacokinetic characteristics and then beneficial effects of RSV. These methodological approaches include RSV nanoencapsulation in lipid nanocarriers or liposomes, nanoemulsions, micelles, insertion into polymeric particles, solid dispersions, and nanocrystals. Moreover, the biological results obtained on several synthetic derivatives containing different substituents, such as methoxylic, hydroxylic groups, or halogens on the RSV aromatic rings, will be described. Results reported in the literature are encouraging but require additional in vivo studies, to support clinical applications.


Assuntos
Resveratrol/administração & dosagem , Resveratrol/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Halogênios/química , Humanos , Lipossomos , Resveratrol/química , Resveratrol/farmacocinética
10.
Bioorg Med Chem ; 23(22): 7302-12, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26526741

RESUMO

The antitumor activity shown by many platinum complexes has produced a strong interest in research of new organometallic compounds having anticancer action. Among the many metal compounds synthesized and tested, those based on titanium have received considerable attention because of their cytotoxic activity against solid tumors. Particularly, new titanocene compounds containing aromatic groups linked to the Cp (cyclopentadienyl ring, C5H5) have been synthetized, such as the titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium dichloride) that displayed promising medium-high cytotoxic activity on breast cancer cell lines. Other titanocene complexes recently synthesized, obtained by replacing the substituent methoxy-aryl of cyclopentadienes of titanocene Y with ethenyl-methoxide or ethenyl-phenoxide, showed increased cytotoxic activity on breast cancer cell lines being more stable compounds. In this paper, we report that new titanocene complexes holding lipophilic groups, for instance a methyl group on benzyl carbon, exhibit improved antiproliferative effect on breast cancer cell line MCF-7. Similar results have been obtained introducing a 5-methoxy naphthyl group to further stabilize the titanocene complexes. These inhibitory effects on breast cancer cells have been ascribed to human topoisomerase I and II inhibition as demonstrated by specific enzymatic assays.


Assuntos
DNA Topoisomerases Tipo I/química , Proteínas de Ligação a DNA/antagonistas & inibidores , Compostos Organometálicos/química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase II/química , Antígenos de Neoplasias/metabolismo , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Células MCF-7 , Microscopia de Fluorescência , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia
11.
Int Urol Nephrol ; 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39052168

RESUMO

Chronic kidney disease (CKD) represents a significant global health challenge, characterized by kidney damage and decreased function. Its prevalence has steadily increased, necessitating a comprehensive understanding of its epidemiology, risk factors, and management strategies. While traditional prognostic markers such as estimated glomerular filtration rate (eGFR) and albuminuria provide valuable insights, they may not fully capture the complexity of CKD progression and associated cardiovascular (CV) risks.This paper reviews the current state of renal and CV risk prediction in CKD, highlighting the limitations of traditional models and the potential for integrating artificial intelligence (AI) techniques. AI, particularly machine learning (ML) and deep learning (DL), offers a promising avenue for enhancing risk prediction by analyzing vast and diverse patient data, including genetic markers, biomarkers, and imaging. By identifying intricate patterns and relationships within datasets, AI algorithms can generate more comprehensive risk profiles, enabling personalized and nuanced risk assessments.Despite its potential, the integration of AI into clinical practice faces challenges such as the opacity of some algorithms and concerns regarding data quality, privacy, and bias. Efforts towards explainable AI (XAI) and rigorous data governance are essential to ensure transparency, interpretability, and trustworthiness in AI-driven predictions.

12.
Bioorg Med Chem Lett ; 23(17): 4990-5, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23860590

RESUMO

It is well known that resveratrol (RSV) displayed cancer-preventing and anticancer properties but its clinical application is limited because of a low bioavailability and a rapid clearance from the circulation. Aim of this work was to synthesize pharmacologically active resveratrol analogs with an enhanced structural rigidity and bioavailability. In particular, we have synthesized a library of 2,3-thiazolidin-4-one derivatives in which a thiazolidinone nucleus connects two aromatic rings. Some of these compounds showed strong inhibitory effects on breast cancer cell growth. Our results indicate that some of thiazolidin-based resveratrol derivatives may become a new potent alternative tool for the treatment of human breast cancer.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Estilbenos/química , Estilbenos/farmacologia , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Antineoplásicos Fitogênicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Resveratrol , Estilbenos/síntese química , Tiazolidinedionas/síntese química
13.
Bioorg Med Chem Lett ; 23(23): 6401-5, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24119558

RESUMO

Resveratrol (3,4',5 tri-hydroxystilbene), a natural plant polyphenol, has gained interest as a non-toxic agent capable of inducing tumor cell death in a variety of cancer types. However, therapeutic application of these beneficial effects remains very limited due to its short biological half-life, labile properties, rapid metabolism and elimination. Different studies were undertaken to obtain synthetic analogs of resveratrol with major bioavailability and anticancer activity. We have synthesized a series 3-chloro-azetidin-2-one derivatives, in which an azetidinone nucleus connects two aromatic rings. Aim of the present study was to investigate the effects of these new 3-chloro-azetidin-2-one resveratrol derivatives on human breast cancer cell lines proliferation. Our results indicate that some azetidin-based resveratrol derivatives may become new potent alternative tools for the treatment of human breast cancer.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Azetidinas/química , Azetidinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Estilbenos/química , Estilbenos/farmacologia , Células 3T3 , Animais , Azetidinas/síntese química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Resveratrol , Estilbenos/síntese química
14.
Life (Basel) ; 13(2)2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36836619

RESUMO

Plant-derived bioactive compounds are gaining wide attention for their multiple health-promoting activities and in particular for their anti-cancer properties. Several studies have highlighted how they can prevent cancer initiation and progression, improve the effectiveness of chemotherapy, and, in some cases, limit some of the side effects of chemotherapy agents. In this paper, we provide an update of the literature on the anti-cancer effects of three extensively studied plant-derived compounds, namely resveratrol, epigallocatechin gallate, and curcumin, with a special focus on the anti-cancer molecular mechanisms inducing apoptosis in the major types of cancers globally.

15.
Cancers (Basel) ; 15(4)2023 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-36831394

RESUMO

Extensive research suggests that curcumin interferes with multiple cell signaling pathways involved in cancer development and progression. This study aimed to evaluate curcumin effects on adrenocortical carcinoma (ACC), a rare but very aggressive tumor. Curcumin reduced growth, migration and activated apoptosis in three different ACC cell lines, H295R, SW13, MUC-1. This event was related to a decrease in estrogen-related receptor-α (ERRα) expression and cholesterol synthesis. More importantly, curcumin changed ACC cell metabolism, increasing glycolytic gene expression. However, pyruvate from glycolysis was only minimally used for lactate production and the Krebs cycle (TCA). In fact, lactate dehydrogenase, extracellular acidification rate (ECAR), TCA genes and oxygen consumption rate (OCR) were reduced. We instead found an increase in Glutamic-Pyruvic Transaminase (GPT), glutamine antiport transporter SLC1A5 and glutaminase (GLS1), supporting a metabolic rewiring toward glutamine metabolism. Targeting this mechanism, curcumin effects were improved. In fact, in a low glutamine-containing medium, the growth inhibitory effects elicited by curcumin were observed at a concentration ineffective in default growth medium. Data from this study prove the efficacy of curcumin against ACC growth and progression and point to the concomitant use of inhibitors for glutamine metabolism to improve its effects.

16.
J Cell Physiol ; 227(5): 2079-88, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21769864

RESUMO

Several substances such as anabolic androgenic steroids (AAS), peptide hormones like insulin-like growth factor-I (IGF-I), aromatase inhibitors and estrogen antagonists are offered via the Internet, and are assumed without considering the potential deleterious effects that can be caused by their administration. In this study we aimed to determine if nandrolone and stanozolol, two commonly used AAS, could have an effect on Leydig cell tumor proliferation and if their effects could be potentiated by the concomitant use of IGF-I. Using a rat Leydig tumor cell line, R2C cells, as experimental model we found that nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and estradiol (E2) production. When used in combination with IGF-I they were more effective than single molecules in inducing aromatase expression. AAS exhibited estrogenic activity and induced rapid estrogen receptor (ER)-dependent pathways involving IGF1R, AKT, and ERK1/2 phosphorylation. Inhibitors for these kinases decreased AAS-dependent aromatase expression. Up-regulated aromatase levels and related E2 production increased cell proliferation as a consequence of increased cyclin E expression. The observation that ER antagonist ICI182,780 was also able to significantly reduce ASS- and AAS + IGF-induced cell proliferation, confirmed a role for estrogens in AAS-dependent proliferative effects. Taken together these data clearly indicate that the use of high doses of AAS, as it occurs in doping practice, enhances Leydig cell proliferation, increasing the risk of tumor development. This risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS and testicular cancer.


Assuntos
Androgênios/farmacologia , Proliferação de Células/efeitos dos fármacos , Estrogênios/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Tumor de Células de Leydig/patologia , Nandrolona/farmacologia , Estanozolol/farmacologia , Neoplasias Testiculares/patologia , Anabolizantes/efeitos adversos , Anabolizantes/farmacologia , Androgênios/efeitos adversos , Animais , Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Linhagem Celular Tumoral , Ciclina E/genética , Ciclina E/metabolismo , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Tumor de Células de Leydig/induzido quimicamente , Masculino , Nandrolona/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Estanozolol/efeitos adversos , Neoplasias Testiculares/induzido quimicamente
17.
J Cell Sci ; 123(Pt 22): 3956-65, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20980388

RESUMO

Steroid production in the adrenal zona glomerulosa is under the control of angiotensin II (Ang II), which, upon binding to its receptor, activates protein kinase C (PKC) within these cells. PKC is a potent inhibitor of the steroidogenic enzyme CYP17. We have demonstrated that, in the ovary, PKC activates expression of FOS, a member of the AP-1 family, and increased expression of this gene is linked to CYP17 downregulation. However, the pathway and the molecular mechanism responsible for the inhibitory effect of PKC on CYP17 expression are not defined. Herein, we demonstrated that Ang II inhibited CYP17 through PKC and ERK1/2-activated FOS and that blocking FOS expression decreased PKC-mediated inhibition. Although CYP17 transcription was activated by the nuclear receptor SF-1, expression of FOS resulted in a decrease in SF-1-mediated gene transcription. FOS physically interacted with the hinge region of SF-1 and modulated its transactivity, thus preventing binding of cofactors such as SRC1 and CBP, which were necessary to fully activate CYP17 transcription. Collectively, these results indicate a new regulatory mechanism for SF-1 transcriptional activity that might influence adrenal zone-specific expression of CYP17, a mechanism that can potentially be applied to other steroidogenic tissues.


Assuntos
Fatores de Transcrição NFI/metabolismo , Esteroide 17-alfa-Hidroxilase/biossíntese , Fator Esteroidogênico 1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Glândulas Suprarrenais/enzimologia , Glândulas Suprarrenais/metabolismo , Sinalização do Cálcio , Técnicas de Cultura de Células , Humanos , Imuno-Histoquímica , Análise em Microsséries , Fatores de Transcrição NFI/genética , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Fator de Transcrição AP-1/genética , Ativação Transcricional , Transfecção
18.
J Enzyme Inhib Med Chem ; 27(4): 609-13, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21883039
19.
Drug Deliv Transl Res ; 12(8): 1881-1894, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35359261

RESUMO

In diabetic patients, the presence of neuropathy, peripheral vascular diseases and ischemia, leads to the formation of foot ulcerations with a higher risk of infection because the normal response to bacterial infection is missing. In the aim to control and treat diabetic foot ulcerations (DFUs), wound dressings that are able to absorb exudate, to prevent infections, and to promote wound healing are needed. For this reason, the aim of the present research was to synthetize a biocompatible hydrogel (called HyDrO-DiAb) composed of carboxymethylcellulose loaded with silver nanoparticles (AgNPs) for the treatment of diabetic foot ulcers. In this study, AgNPs were obtained by a green synthesis and, then, were dissolved in a CMC hydrogel that, after a freeze drying process, becomes a flexible and porous structure. The in vitro and in ex vivo wound healing activity of the obtained HyDrO-DiAb hydrogel was evaluated.


Assuntos
Pé Diabético , Nanopartículas Metálicas , Humanos , Hidrogéis/química , Nanopartículas Metálicas/química , Prata/química , Cicatrização
20.
Cancers (Basel) ; 14(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36010877

RESUMO

The aim of this study was to investigate the metabolic changes that occur in adrenocortical cancer (ACC) cells in response to the modulation of Estrogen Related Receptor (ERR)α expression and the impact on ACC progression. Proteomics analysis and metabolic profiling highlighted an important role for ERRα in the regulation of ACC metabolism. Stable ERRα overexpression in H295R cells promoted a better mitochondrial fitness and prompted toward a more aggressive phenotype characterized by higher Vimentin expression, enhanced cell migration and spheroids formation. By contrast, a decrease in ERRα protein levels, by molecular (short hairpin RNA) and pharmacological (inverse agonist XCT790) approaches modified the energetic status toward a low energy profile and reduced Vimentin expression and ability to form spheroids. XCT790 produced similar effects on two additional ACC cell lines, SW13 and mitotane-resistant MUC-1 cells. Our findings show that ERRα is able to modulate the metabolic profile of ACC cells, and its inhibition can strongly prevent the growth of mitotane-resistant ACC cells and the progression of ACC cell models to a highly migratory phenotype. Consequently, ERRα can be considered an important target for the design of new therapeutic strategies to fight ACC progression.

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