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1.
Eur J Med Chem ; 181: 111583, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400710

RESUMO

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4-9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4).


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Desenho de Drogas , Feminino , Humanos , Simulação de Acoplamento Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Inibidores da Topoisomerase I/química , Moduladores de Tubulina/química
2.
J Exp Clin Cancer Res ; 38(1): 335, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370872

RESUMO

BACKGROUND: The chemical carcinogen 3-methylcholanthrene (3MC) binds to the aryl hydrocarbon receptor (AHR) that regulates the expression of cytochrome P450 (CYP) enzymes as CYP1B1, which is involved in the oncogenic activation of environmental pollutants as well as in the estrogen biosynthesis and metabolism. 3MC was shown to induce estrogenic responses binding to the estrogen receptor (ER) α and stimulating a functional interaction between AHR and ERα. Recently, the G protein estrogen receptor (GPER) has been reported to mediate certain biological responses induced by endogenous estrogens and environmental compounds eliciting an estrogen-like activity. METHODS: Molecular dynamics and docking simulations were performed to evaluate the potential of 3MC to interact with GPER. SkBr3 breast cancer cells and cancer-associated fibroblasts (CAFs) derived from breast tumor patients were used as model system. Real-time PCR and western blotting analysis were performed in order to evaluate the activation of transduction mediators as well as the mRNA and protein levels of CYP1B1 and cyclin D1. Co-immunoprecipitation studies were performed in order to explore the potential of 3MC to trigger the association of GPER with AHR and EGFR. Luciferase assays were carried out to determine the activity of CYP1B1 promoter deletion constructs upon 3MC exposure, while the nuclear shuttle of AHR induced by 3MC was assessed through confocal microscopy. Cell proliferation stimulated by 3MC was determined as biological counterpart of the aforementioned experimental assays. The statistical analysis was performed by ANOVA. RESULTS: We first ascertained by docking simulations the ability of 3MC to interact with GPER. Thereafter, we established that 3MC activates the EGFR/ERK/c-Fos transduction signaling through both AHR and GPER in SkBr3 cells and CAFs. Then, we found that these receptors are involved in the up-regulation of CYP1B1 and cyclin D1 as well as in the stimulation of growth responses induced by 3MC. CONCLUSIONS: In the present study we have provided novel insights regarding the molecular mechanisms by which 3MC may trigger a physical and functional interaction between AHR and GPER, leading to the stimulation of both SkBr3 breast cancer cells and CAFs. Altogether, our results indicate that 3MC may engage both GPER and AHR transduction pathways toward breast cancer progression.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Metilcolantreno/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metilcolantreno/química , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Transporte Proteico , Receptores de Hidrocarboneto Arílico/química , Receptores Estrogênicos/química , Receptores Acoplados a Proteínas-G/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
3.
Cells ; 8(6)2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207943

RESUMO

The inhibition of the G protein-coupled estrogen receptor (GPER) offers promising perspectives for the treatment of breast tumors. A peptide corresponding to part of the hinge region/AF2 domain of the human estrogen receptor α (ERα17p, residues 295-311) exerts anti-proliferative effects in various breast cancer cells including those used as triple negative breast cancer (TNBC) models. As preliminary investigations have evoked a role for the GPER in the mechanism of action of this peptide, we focused our studies on this protein using SkBr3 breast cancer cells, which are ideal for GPER evaluation. ERα17p inhibits cell growth by targeting membrane signaling. Identified as a GPER inverse agonist, it co-localizes with GPER and induces the proteasome-dependent downregulation of GPER. It also decreases the level of pEGFR (phosphorylation of epidermal growth factor receptor), pERK1/2 (phosphorylation of extracellular signal-regulated kinase), and c-fos. ERα17p is rapidly distributed in mice after intra-peritoneal injection and is found primarily in the mammary glands. The N-terminal PLMI motif, which presents analogies with the GPER antagonist PBX1, reproduces the effect of the whole ERα17p. Thus, this motif seems to direct the action of the entire peptide, as highlighted by docking and molecular dynamics studies. Consequently, the tetrapeptide PLMI, which can be claimed as the first peptidic GPER disruptor, could open new avenues for specific GPER modulators.


Assuntos
Fragmentos de Peptídeos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Neoplasias de Mama Triplo Negativas/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptor alfa de Estrogênio/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteína Adaptadora GRB2/química , Proteína Adaptadora GRB2/metabolismo , Humanos , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Domínios de Homologia de src
4.
Pharmaceutics ; 11(5)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035595

RESUMO

An in-depth analysis of nanotechnology applications for the improvement of solubility, distribution, bioavailability and stability of reverse transcriptase inhibitors is reported. Current clinically used nucleoside and non-nucleoside agents, included in combination therapies, were examined in the present survey, as drugs belonging to these classes are the major component of highly active antiretroviral treatments. The inclusion of such agents into supramolecular vesicular systems, such as liposomes, niosomes and lipid solid NPs, overcomes several drawbacks related to the action of these drugs, including drug instability and unfavorable pharmacokinetics. Overall results reported in the literature show that the performances of these drugs could be significantly improved by inclusion into nanosystems.

5.
Nat Prod Res ; : 1-4, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31104489

RESUMO

Salvia miltiorrhiza Bunge extract was investigated for the first time for its inhibitory activity against pancreatic lipase (PL), an important enzyme involved in the digestion of dietary fats. It showed a concentration-dependent activity with an IC50 value of 3.54 ± 0.22 mg/mL. Two compounds, cryptotanshinone and tanshinone IIA (the major lipophilic constituents of S. miltiorrhiza), have been selected as potential ligands of PL. Cryptotanshinone showed a higher lipase inhibitory activity (IC50 = 6.86 ± 0.43 µM) compared to the parent tanshinone IIA. Molecular docking studies were undertaken to establish whether a direct interaction of the principal constituents of the S. miltiorrhiza extract with the human pancreatic lipase could be evoked. All these findings provided new insights into the understanding of the interactions between natural constituents of S. miltiorrhiza extract and PL, also suggesting that cryptotanshinone could be used as lead compound for the development of efficacious PL inhibitors.

6.
J Nutr Biochem ; 69: 151-162, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31096072

RESUMO

Recently the attention of the scientific community has focused on the ability of polyphenols to counteract adverse epigenetic regulation involved in the development of complex conditions such as obesity. The aim of this study was to investigate the epigenetic mechanisms underlying the anti-adiposity effect of Quercetin (3,3',4',5,7-pentahydroxyflavone) and of one of its derivatives, Q2 in which the OH groups have been replaced by acetyl groups. In 3 T3-L1 preadipocytes, Quercetin and Q2 treatment induce chromatin remodeling and histone modifications at the 5' regulatory region of the two main adipogenic genes, c/EBPα and PPARγ. Chromatin immunoprecipitation assays revealed a concomitant increase of histone H3 di-methylation at Lys9, a typical mark of repressed gene promoters, and a decrease of histone H3 di-methylation at Lys 4, a mark of active transcription. At the same time, both compounds inhibited histone demethylase LSD1 recruitment to the 5' region of c/EBPα and PPARγ genes, a necessary step for adipogenesis. The final effect is a significant reduction in c/EBPα and PPARγ gene expression and attenuated adipogenesis. Q2 supplementation in rats reduced the gain in body weight and in white adipose tissue, as well as the increase in adipocyte size determined by high fat diet. Moreover, Q2 improved dyslipidemia, glucose tolerance and decreased the hepatic lipid accumulation by activating the expression of beta-oxidation related genes. Our data suggest that Q2, as well as Quercetin, has the potential to revert the unfavorable epigenomic profiles associated with obesity onset. This opens the possibility to use these compounds in targeted prevention strategies against obesity.

7.
J Food Sci Technol ; 56(2): 614-623, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30906019

RESUMO

The thermal and light stability of linseed oil has been studied by monitoring the concentrations of fatty acids and lignans, as main nutraceutical components. Linseed oil was subjected to stressing light and temperature conditions, in accordance with the ICH international rules, and monitored by UV-vis spectroscopy and HPLC-DAD. The change of UV spectra along the photodegradation tests, setting the irradiation power at 350 W/m2, confirmed a significant overall sensitivity of linseed oil to light. At the same time, the HPLC determination of the major fatty acids showed a marked variation in their concentration up to a residual concentration of 62.3 and 67.2% for α-linolenic and linoleic acid, respectively, after 18 h. In contrast, thermal tests at 60 °C showed some stability, with a concentration of residual fatty acids in the range 82-95% after 48 h. The examined lignans showed significant stability when exposed to both light and heat. Several photoprotection approaches have been also studied to increase the photostability of linseed oil. A significant increase in the stability of fatty acids has been observed using amber glass containers or ascorbic acid or by combining the two protection factors.

8.
Molecules ; 24(3)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717348

RESUMO

HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor functions, preventing the viral spread toward AIDS. Due to the capability of HIV to develop resistance by switching from CCR5 to CXCR4, dual co-receptor antagonists could represent the next generation of AIDS prophylaxis drugs. We herein present a survey on relevant results published in the last few years on compounds acting simultaneously on both co-receptors, potentially useful as preventing agents or in combination with classical anti-retroviral drugs based therapy.


Assuntos
Fármacos Anti-HIV/química , Infecções por HIV/tratamento farmacológico , Receptores CCR5/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Fármacos Anti-HIV/uso terapêutico , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/uso terapêutico , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Maraviroc/química , Maraviroc/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Receptores CCR5/genética , Receptores CXCR4/genética
9.
Pharmaceutics ; 11(1)2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30641992

RESUMO

: The stability profile of a new 1,4-dihydropyridine derivative (DHP), representative of a series with a hexahydroquinoline ring, was studied to design light-stable liquid formulations. This molecule, named M3, has been shown among the analogs to have a high capacity to block both L- and T-type calcium channels. The ethanol solution of the drug was subjected to a photodegradation test, in accordance with standard rules. The concentrations of the drug and its byproducts were estimated using multivariate curve resolution, applied to the spectral data collected during the test. The improvement of both the photostability and water solubility of M3 was investigated by adding the surfactant polysorbate 20 in a 1:5 ratio to aqueous solutions of the drug. These formulations were exposed to stressing light in containers of bleu polyethylene terephthalate (PET), amber PET, and covered amber PET. The best results were obtained when using the covered amber PET container, reaching a degradation percentage of the drug less than 5% after 12 h under an irradiance power of 450 W/m². The stability of the compound was compared to that of nimodipine (NIM) under the same conditions.

10.
Eur J Med Chem ; 151: 121-144, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29609119

RESUMO

The present review lists the papers and patents dealing with the class of polycondensed heterocycles called benzopyrroloxazines published in the last decades. The survey is limited to substances characterized by the presence of a bridgehead N atom, which means that the present N atom serves to connect different rings within the same molecule. In the case of benzopyrroloxazines, the bridgehead N atom belongs at the same time to the pyrrole and oxazine rings. All other compounds not possessing this feature were kept out accordingly. Relevant synthetic methods to such compounds have been outlined. Many different biological properties have been attributed to several functionalized derivatives of these heterocycles and cited within the review.


Assuntos
Descoberta de Drogas , Oxazinas/química , Oxazinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Técnicas de Química Sintética/métodos , Descoberta de Drogas/métodos , Humanos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Nitrogênio/química , Nitrogênio/farmacologia , Oxazinas/síntese química , Pirróis/síntese química , Viroses/tratamento farmacológico
11.
Molecules ; 23(4)2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29649162

RESUMO

The physiological responses to estrogen hormones are mediated within specific tissues by at least two distinct receptors, ER and ER. Several natural and synthetic molecules show activity by interacting with these proteins. In particular, a number of vegetal compounds known as phytoestrogens shows estrogenic or anti-estrogenic activity. The majority of these compounds belongs to the isoflavones family and the most representative one, genistein, shows anti-proliferative effects on various hormone-sensitive cancer cells, including breast, ovarian and prostate cancer. In this work we describe the identification of structurally related homoisoflavones isolated from Leopoldia comosa (L.) Parl. (L. comosa), a perennial bulbous plant, potentially useful as hormonal substitutes or complements in cancer treatments. Two of these compounds have been selected as potential ligands of estrogen receptors (ERs) and the interaction with both isoforms of estrogen receptors have been investigated through molecular docking on their crystallographic structures. The results provide evidence of the binding of these compounds to the target receptors and their interactions with key residues of the active sites of the two proteins, and thus they could represent suitable leads for the development of novel tools for the dissection of ER signaling and the development of new pharmacological treatments in hormone-sensitive cancers.


Assuntos
Hyacinthus/química , Isoflavonas/química , Receptores Estrogênicos/metabolismo , Domínio Catalítico/efeitos dos fármacos , Isoflavonas/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Receptores Estrogênicos/química
12.
Molecules ; 23(2)2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29385738

RESUMO

BACKGROUND: Despite the progress achieved by anti-retroviral drug research in the last decades, the discovery of novel compounds endowed with selective antiviral activity and reduced side effects is still a necessity. At present, the most urgent requirement includes the improvement of HIV (Human Immunodeficiency Virus) prevention and sexual transmission and the development of new drugs to treat the chronic lifelong infection. METHODS: Six chloro-1,4-dimethyl-9H-carbazoles (2a,b-4a,b) have been prepared following opportunely modified known chemical procedures and tested in luciferase and Escherichia coli ß-galactosidase expressing CD4⁺, CXCR4⁺, CCR5⁺ TZM-bl cells. RESULTS AND CONCLUSION: a preliminary biological investigation on the synthesized small series of chloro-1,4-dimethyl-9H-carbazoles has been carried out. Among all tested compounds, a nitro-derivative (3b) showed the most interesting profile representing a suitable lead for the development of novel anti-HIV drugs.


Assuntos
Fármacos Anti-HIV , Carbazóis , Infecções por HIV/prevenção & controle , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Carbazóis/síntese química , Carbazóis/química , Carbazóis/farmacologia , Linhagem Celular , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos
13.
Future Med Chem ; 9(17): 2011-2028, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29076772

RESUMO

AIM: Quercetin (Q1) is a flavonoid widely present in plants and endowed with several pharmacological properties mostly due to its antioxidant potential. Q1 shows anticancer activity and could be useful in cancer prevention. On the other hand, Q1 is poorly soluble in water and unstable in physiological systems, and its bioavailability is very low. METHODS: A small set of Q1 derivatives (Q2-Q9) has been synthesized following opportunely modified chemical procedures previously reported. Anticancer activity has been evaluated by MTT assay. Human Topoisomerases inhibition has been performed by direct enzymatic assays. Apoptosis has been evaluated by TUNEL assay. ROS production and scavenging activity have been determined by immunofluorescence. RESULTS: The anticancer profile of a small library of Q1 analogues, in which the OH groups were all or partially replaced with hydrophobic functional groups, has been evaluated. Two of the studied compounds demonstrated an interesting cytotoxic profile in two breast cancer models showing the capability to inhibit human Topoisomerases. CONCLUSION: The studied compounds represent suitable leads for the development of innovative anticancer drugs. [Formula: see text].


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases/metabolismo , Quercetina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Inibidores da Topoisomerase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , 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 , Humanos , Simulação de Acoplamento Molecular , Quercetina/síntese química , Quercetina/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química , Células Tumorais Cultivadas
14.
Acta Pharm ; 67(3): 341-355, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28858832

RESUMO

This paper describes the synthesis of 1,4-dihydropyridine compounds (DHPs) endowed with good muscle relaxant activity and stability to light. Six new condensed DHPs were synthesized by the microwave irradiation method. A long-chain ester moiety [2-(methacryloyloxy)ethyl] and various substituents on the phenyl ring were demonstrated to affect the muscle relaxant activity occurring in isolated rabbit gastric fundus smooth muscle strips. Forced photodegradation conditions were applied to the molecules according to the ICH rules. The degradation profile of the drugs was monitored by spectrophotometry coupled with the multivariate curve resolution technique. Formation of the oxidized pyridine derivative was observed for all the studied DHPs, except for one compound, which showed very fast degradation and formation of a second photo-product. Pharmacological tests on the molecules showed a good muscle relaxing effect, with a mechanism similar to that of nifedipine, however, proving to be more stable to light.


Assuntos
Di-Hidropiridinas/química , Músculo Liso/efeitos dos fármacos , Fármacos Neuromusculares/química , Animais , Técnicas In Vitro , Luz , Fotólise , Coelhos , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 139: 519-530, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-28826086

RESUMO

CXCR4 (C-X-C Chemokine Receptor type 4) and its natural ligand SDF-1α (Stromal-Derived-Factor-1α) are involved in a number of physiological and pathological processes including cancer spread and progression. Over the past few years, numerous CXCR4 antagonists have been identified and currently are in different development stages as potential agents for the treatment of several diseases involving the CXCR4/SDF-1α axis. Herein, we focus on small molecules reported in literature between 2013 and 2017, claimed as CXCR4 antagonists and potentially useful in the treatment of cancer and other diseases where this receptor is involved. Most of the compounds resulted from a chemical optimization of previously identified molecules and some of them could represent suitable candidates for the development of advanced anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
16.
Oncotarget ; 7(40): 65109-65124, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27556298

RESUMO

Stromal Derived Factor-1α (SDF-1α) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) γ, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPARγ-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPARγ downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPARγ agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPARγ-mediated, since it was reversed in the presence of the PPARγ antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1α, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPARγ in inhibiting breast cancer progression and further highlight the utility of PPARγ ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , PPAR gama/metabolismo , Receptores CXCR4/biossíntese , Elementos de Resposta/genética , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Ligantes , Regiões Promotoras Genéticas/genética , Receptores CXCR4/genética
17.
Mini Rev Med Chem ; 16(9): 762-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26996620

RESUMO

Titanium dioxide (TiO2) is a natural oxide of the element titanium with low toxicity, and negligible biological effects. The classification as bio-inert material has given the possibility to normal-sized (>100 nm) titanium dioxide particles (TiO2-NPs) to be extensively used in food products and as ingredients in a wide range of pharmaceutical products and cosmetics, such as sunscreens and toothpastes. Therefore, human exposure may occur through ingestion and dermal penetration, or through inhalation route, during both the manufacturing process and use. In spite of the extensively use of TiO2-NPs, the biological effects and the cellular response mechanisms are still not completely elucidated and thus a deep understanding of the toxicological profile of this compound is required. The main mechanism underlining the toxicity potentially triggered by TiO2-NPs seems to involve the reactive oxygen species (ROS) production, resulting in oxidative stress, inflammation, genotoxicity, metabolic change and potentially carcinogenesis. The extent and type of cell damage strongly depend on chemical and physical characteristics of TiO2-NPs, including size, crystal structure and photo-activation. In this mini-review, we would like to discuss the latest findings on the adverse effects and on potential human health risks induced by TiO2-NPs exposure.


Assuntos
Nanopartículas/efeitos adversos , Titânio/efeitos adversos , Cosméticos/efeitos adversos , Cosméticos/metabolismo , Inocuidade dos Alimentos , Humanos , Nanopartículas/química , Nanopartículas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Titânio/química , Titânio/metabolismo
18.
Mini Rev Med Chem ; 16(8): 644-50, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26955877

RESUMO

Design and discovery of new classes of anticancer agents with unique mechanisms of action is an urgent medical need. During the past several years, a series of salicylhydrazide class of compounds were reported to possess remarkable potency in a large panel of cancer cell lines from different tumor origins. In particular, the optimized lead compound, SC144, was further investigated and selected as a valuable drug candidate endowed with favorable pharmacokinetic and antiproliferative properties in various in vitro and in vivo xenograft models. This lead compound is active in cells resistant to conventional chemotherapies, synergistic with several standard-of-care drugs, and possesses an unique mechanism acting through the inhibition of the gp130-STAT3-survivin axis. Because of this novel mechanism, clinical development of SC144 will provide new therapeutic options for diverse cancers.


Assuntos
Antineoplásicos/farmacologia , Hidrazinas/farmacocinética , Neoplasias/tratamento farmacológico , Quinoxalinas/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Estrutura Molecular , Neoplasias/patologia , Quinoxalinas/síntese química , Quinoxalinas/química
19.
Future Med Chem ; 8(2): 93-106, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26807787

RESUMO

BACKGROUND: Stromal-derived-factor-1 (SDF-1) and the G-protein-coupled receptor CXCR4 are involved in several physiological and pathological processes including breast cancer spread and progression. Several CXCR4 antagonists have currently reached advanced development stages as potential therapeutic agents for different diseases. RESULTS: A small series of novel CXCR4 ligands, based on a 2-(1H-indol-1-yl)-benzohydrazide scaffold, has been designed and synthesized. The interaction with CXCR4-active site was predicted by molecular docking and confirmed by whole cell-based [(125)I]-SDF-1 ligand competition binding assays. One of the synthesized compounds was particularly active in blocking SDF-1-induced breast cancer cell motility, proliferation and downstream signaling activation in different breast cancer cell models and coculture systems. CONCLUSION: The newly synthesized compounds represent suitable leads for the development of innovative therapeutic agents targeting CXCR4.


Assuntos
Antineoplásicos/química , Hidrazinas/química , Receptores CXCR4/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Domínio Catalítico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL12/antagonistas & inibidores , Quimiocina CXCL12/metabolismo , Desenho de Drogas , Feminino , Humanos , Hidrazinas/síntese química , Hidrazinas/toxicidade , Ligantes , Simulação de Acoplamento Molecular , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Eur J Pharm Sci ; 82: 161-70, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26631584

RESUMO

The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with ß-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10(-8)M÷10(-6)M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10(-10)M and 10(-8)÷10(-6)M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both ß1/ß2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Quercetina/farmacologia , Animais , Anti-Hipertensivos/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Suco Gástrico/metabolismo , Coração/efeitos dos fármacos , Coração/fisiologia , Secreções Intestinais/metabolismo , Modelos Moleculares , Pancreatina/metabolismo , Pepsina A/metabolismo , Quercetina/análogos & derivados , Quercetina/química , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo
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