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1.
Plants (Basel) ; 10(5)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919433

RESUMO

Rindera graeca is a rare endemic plant where in vitro culture has been used in order to investigate bioactive metabolites. Phytochemical study of the in vitro shoots and hairy roots led to the isolation of seven phenolic derivatives and the unusual furano-naphthoquinone rinderol. R. graeca was also analyzed for its pyrrolizidine alkaloids content by LC-MS, and it was found to contain echinatine together with echinatine and rinderine N-oxides. Rinderol, isolated only from in vitro hairy root culture for the first time in the genus, revealed promising bioactivities. It was evaluated in vitro against a panel of microorganisms, showing very strong activity specifically against Gram-positive bacteria (MIC values 0.98 × 10-2-1.18 µg/mL) as well as very interesting antiproliferative effect against the human non-small-cell bronchopulmonary carcinoma cell line NSCLC-N6-L16 and the epidermoid lung cancer cell line A549. These findings were compared with the chemical profile of the plant from nature, while this study is the first to report on the effects of R. graeca extracts obtained from in vitro culture, providing a valuable contribution to the scientific community towards this sustainable method of production of potential bioactive molecules.

2.
Cancers (Basel) ; 11(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374910

RESUMO

Targeting epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKI) has been widely exploited to disrupt aberrant phosphorylation flux in cancer. However, a bottleneck of potent TKIs is the acquisition of drug resistance mutations, secondary effects, and low ability to attenuate tumor progression. We have developed an alternative means of targeting EGFR that relies on protein degradation through two consecutive routes, ultimately leading to cancer cell detachment-related death. We describe furfuryl derivatives of 4-allyl-5-[2-(4-alkoxyphenyl)-quinolin-4-yl]-4H-1,2,4-triazole-3-thiol that bind to and weakly inhibit EGFR tyrosine phosphorylation and induce strong endocytic degradation of the receptor in cancer cells. The compound-promoted depletion of EGFR resulted in the sequestration of non-phosphorylated Bim, which no longer ensured the integrity of the cytoskeleton machinery, as shown by the detachment of cancer cells from the extracellular matrix (ECM). Of particular note, the longer CH3(CH2)n chains in the terminal moiety of the anti-EGFR molecules confer higher hydrophobicity in the allosteric site located in the immediate vicinity of the catalytic pocket. Small compounds accelerated and enhanced EGFR and associated proteins degradation during EGF and/or glutamine starvation of cultures, thereby demonstrating high potency in killing cancer cells by simultaneously modulating signaling and metabolic pathways. We propose a plausible mechanism of anti-cancer action by small degraders through the allosteric site of EGFR. Our data represent a rational and promising perspective in the treatment of aggressive tumors.

3.
Mar Drugs ; 17(6)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234456

RESUMO

The most common sterol in fungi is ergosterol, which has frequently been investigated in human pathogenic fungal strains. This sterol, and others isolated from fungal strains, has also demonstrated cytotoxicity against cancer cell lines and antimicrobial activities. Marine fungi can produce high amounts of bioactive compounds. So, a screening was performed to study sterol composition using GC/MS in 19 marine fungal strains and ergosterol was always the major one. One strain, Clonostachys rosea MMS1090, was selected due to its high amount of eburicol and a one strain many compounds approach was performed on seven culture media to optimize its production. After purification and structural identification by NMR, eburicol was assessed against four cancer cell lines, MCF-7, MDA-MB-231, NSCLC-N6-L16 and A549, and seven human pathogenic bacteria Staphylococcus aureus, Bacillus sp., Bacillus cereus, Listeria ivanovii, Escherichia coli, Citrobacter freundii and Salmonella spp. The most significant activity was cytotoxicity against MCF-7 cells (2 µM). This is the first report of such an accumulation of eburicol in the marine fungal strain C. rosea confirming its potential in the production of bioactive lipids.


Assuntos
Anti-Infecciosos/farmacologia , Organismos Aquáticos/metabolismo , Proliferação de Células/efeitos dos fármacos , Fungos/metabolismo , Lanosterol/análogos & derivados , Esteroides/metabolismo , Esteroides/farmacologia , Células A549 , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Lanosterol/farmacologia , Células MCF-7 , Testes de Sensibilidade Microbiana/métodos
4.
Chembiochem ; 20(17): 2255-2261, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-30969460

RESUMO

A family of bi- and tetrametallic gold(I) phosphine dithiocarbamate complexes were synthesized, starting from cyclam and dimethylcyclam polyazamacrocycles, respectively, along with their monometallic gold(I) chloridophosphine precursors. Their antiproliferative properties were evaluated on two cancer cell lines (A549 and NSCLC-N6-L16). Most of the mono- and bimetallic complexes displayed strong activities and, in particular, one bimetallic derivative showed antiproliferative properties in the low micromolar range. Insights into the structure-activity relationships are given, along with determination of the thioredoxin reductase inhibition potential, two-photon imaging of the fluorescent derivatives, and evaluation of gold uptake.


Assuntos
Antineoplásicos/síntese química , Ouro/farmacocinética , Fosfinas , Tiocarbamatos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imagem Óptica , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores
5.
Drug Discov Today ; 23(2): 409-415, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29031622

RESUMO

Protein kinases constitute a large group of enzymes in eukaryotes and have an important role in many cellular processes. Several of these proteins are active kinases, such as haploid germ cell-specific nuclear protein kinase (Haspin), an atypical eukaryotic protein kinase that lacks sequence similarity with other eukaryotic protein kinases. Haspin is a serine/threonine kinase that associates with chromosome and phosphorylates threonine 3 of histone 3 during mitosis. Haspin overexpression or deletion results in defective mitosis. It has been shown that Haspin inhibitors have potent anti-tumoral effects. Given that the only Haspin substrate is threonine 3 of histone 3, inhibition of Haspin might have fewer adverse effects compared with other anticancer agents. Here, we highlight the chemical structures and actions of currently known Haspin inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Cromossomos/efeitos dos fármacos , Histonas/metabolismo , Humanos , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo
6.
Fitoterapia ; 115: 9-14, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27659390

RESUMO

Two new natural products, 5-O-[ß-D-apiofuranosyl-(1→6)-ß-d-glucopyranosyl]-1-isoindolinone (1) as well as N-(2E)-3-[(2S,3R)-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-7-methoxy-2,3-dihydro-1-benzofuran-5-yl]acryloylglycine (2), along with four known compounds (3-6), were isolated from the methanolic extract of Cordia alliodora root bark. Furthermore, the methanolic extract of Cordia colloccoca leaves, afforded the known flavonoids afzelin (7) and quercitrin (8). The isolated secondary metabolites were assayed for their antimicrobial activities against a panel of 6g positive and negative bacteria and three human pathogenic fungi. Moreover, their antiproliferative effect was also evaluated in vitro against the human non-small-cell bronchopulmonary carcinoma line NSCLC-N6, the epidermoid lung cancer cell line A549 as well as the normal human skin fibroblast cell line (AG01523).


Assuntos
Cordia/química , Indóis/química , Extratos Vegetais/química , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Cordia/classificação , Fibroblastos/efeitos dos fármacos , Fungos/efeitos dos fármacos , Humanos , Indóis/isolamento & purificação , Manosídeos/química , Manosídeos/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Casca de Planta/química , Folhas de Planta/química , Raízes de Plantas/química , Proantocianidinas/química , Proantocianidinas/isolamento & purificação , Quercetina/análogos & derivados , Quercetina/química , Quercetina/isolamento & purificação
7.
Anticancer Res ; 36(4): 1621-30, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27069139

RESUMO

A series of (imidazo[1,2-a]pyrazin-6-yl)ureas were synthesized through 6-aminoimidazo[1,2-a]pyrazine as a key intermediate. 1-(Imidazo[1,2-a]pyrazin-6-yl)-3-(4-methoxy - phenyl)urea displayed a cytostatic activity against a non-small cell lung cancer cell line and was chosen for further mechanistic studies. Growth kinetics highlighted a selective dose-dependent response of P53-mutant NSCLC-N6-L16 cell line and overexpression of TP53 gene induced by this compound. These pharmacological data suggest a promising reactivation of p53 mutant in NSCLC-N6-L16 cell line.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Pirazinas/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Células 3T3 BALB , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Proteína Supressora de Tumor p53/genética
8.
Sci Rep ; 6: 21088, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26883293

RESUMO

Activation of cell signaling by reactive chemicals and pollutants is an important issue for human health. It has been shown that lipophilic nitro-benzoxadiazole (NBD) compounds rapidly move across the plasma membrane and enhance Epidermal Growth Factor Receptor (EGFR) tyrosine phosphorylation in cancer cells. Unlike ligand-dependent activation, the mechanism of this induction relies on the generation of hydrogen peroxide, which is involved in the activation of the catalytic site of the receptor and the inactivation of protein tyrosine phosphatase PTP-1B. Production of H2O2 during redox transformation of NBD compounds is associated with the transition of a monomeric form of Cu/Zn superoxide dismutase 1 (SOD1) to stable dimers. The highly stable and functionally active SOD1 dimer, in the absence of adequate activities in downstream reactions, promotes the disproportionate production and accumulation of intracellular hydrogen peroxide shortly after exposure to NBD compounds. The intrinsic fluorescence of small compounds was used to demonstrate their binding to SOD1. Our data indicate that H2O2 and concomitantly generated electrophilic intermediates behave as independent entities, but all contribute to the biological reactivity of NBD compounds. This study opens a promising path to identify new biomarkers of oxidative/electrophilic stress in the progression of cancer and other diseases.

9.
Mar Drugs ; 13(9): 5606-28, 2015 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-26404323

RESUMO

Lipids from the proliferative macroalgae Ulva armoricana (Chlorophyta) and Solieria chordalis (Rhodophyta) from Brittany, France, were investigated. The total content of lipids was 2.6% and 3.0% dry weight for U. armoricana and S. chordalis, respectively. The main fractions of S. chordalis were neutral lipids (37%) and glycolipids (38%), whereas U. armoricana contained mostly neutral lipids (55%). Polyunsaturated fatty acids (PUFA) represented 29% and 15% of the total lipids in U. armoricana and S. chordalis, respectively. In both studied algae, the phospholipids were composed of PUFA for 18%. In addition, PUFA were shown to represent 9% and 4.5% of glycolipids in U. armoricana and S. chordalis, respectively. The essential PUFA were 16:4n-3, 18:4n-3, 18:2n-3, 18:2n-6, and 22:6n-3 in U. armoricana, and 20:4n-6 and 20:5n-3 in S. chordalis. It is important to notice that six 2-hydroxy-, three 3-hydroxy-, and two monounsaturated hydroxy fatty acids were also identified and may provide a chemotaxonomic basis for algae. These seaweeds contained interesting compounds such as squalene, α-tocopherol, cholest-4-en-3-one and phytosterols. The antiproliferative effect was evaluated in vitro on human non-small-cell bronchopulmonary carcinoma line (NSCLC-N6) with an IC50 of 23 µg/mL for monogalactosyldiacylglycerols isolated from S. chordalis and 24 µg/mL for digalactosyldiacylglycerols from U. armoricana. These results confirm the potentialities of valorization of these two species in the fields of health, nutrition and chemotaxonomy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ácidos Graxos/química , Lipídeos/química , Alga Marinha/química , Esteróis/química , Ulva/química , Antineoplásicos Fitogênicos/química , França
10.
Sci Rep ; 5: 10356, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-26011298

RESUMO

Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fosfoproteínas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Reação em Cadeia da Polimerase em Tempo Real , Triazinas/química , Triazinas/uso terapêutico , Triazinas/toxicidade , Proteína Supressora de Tumor p53/genética
11.
Arch Dermatol Res ; 307(3): 211-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25556843

RESUMO

The immunosuppressive properties of Benzophenone-4, an UV-filter and three ingredients, Allantoin, Bisabolol and Enoxolon used in sunscreen formulation, previously characterized as anti-inflammatory compounds, are studied. The results of this study demonstrate that four tested molecules have effects on DCs and T cells which are the most important cells of the immune system. The impact is also visible on keratinocyte cells which are in the direct contact with skin sunscreens. Each ingredient should be used with caution at reduced doses or even removed from some cosmetic preparations, such as sunscreens.


Assuntos
Células Dendríticas/efeitos dos fármacos , Imunossupressores/farmacologia , Pele/efeitos dos fármacos , Protetores Solares/farmacologia , Linfócitos T/efeitos dos fármacos , Alantoína/farmacologia , Benzofenonas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Dendríticas/imunologia , Ácido Glicirretínico/farmacologia , Humanos , Ativação Linfocitária , Sesquiterpenos Monocíclicos , Sesquiterpenos/farmacologia , Pele/patologia , Linfócitos T/imunologia
12.
Anticancer Res ; 34(9): 4797-806, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25202060

RESUMO

Despite progress in chemotherapeutic agents, non-small cell lung cancers (NSCLC) still have a poor survival rate. Thus, development of new therapeutic strategies, specifically against cancer cells is still required. For this purpose, we treated the non-small cell lung cancer cell line NSCLC-N6 with the natural product cucurbitacin D (CucD) - extracted from the plant Ecballium elaterium in order first to assess its in vitro cytotoxicity, but also to study the genetic changes that it could bring out. CucD has shown a blocking in the G1 phase of the cell cycle in NSCLC-N6 cells prior to apoptotic cell death. The reverse transcriptase-polymerase chain reaction-differential display (RT-PCR-DD) technique was also applied on treated cells to elucidate the genetic mechanisms involved. We revealed an overexpression of Cyclin-dependent kinase 1 (CDK1) mRNA after treatment and, with the use of antisense oligonucleotides, an effective role in the proliferation arrest of NSCLC-N6 cells. The present study provides new insights about the mechanisms of proliferation arrest in tumor cells and open new ways of treatment to target tumor growth.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteína Quinase CDC2/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Triterpenos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , RNA Mensageiro/genética , Regulação para Cima
13.
Sci Rep ; 4: 3977, 2014 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-24496106

RESUMO

Peptide ligand-induced dimerization of the extracellular region of the epidermal growth factor receptor (sEGFR) is central to the signal transduction of many cellular processes. A small molecule microarray screen has been developed to search for non-peptide compounds able to bind to sEGFR. We describe the discovery of nitro-benzoxadiazole (NBD) compounds that enhance tyrosine phosphorylation of EGFR and thereby trigger downstream signaling pathways and other receptor tyrosine kinases in cancer cells. The protein phosphorylation profile in cells exposed to NBD compounds is to some extent reminiscent of the profile induced by the cognate ligand. Experimental studies indicate that the small compounds bind to the dimerization domain of sEGFR, and generate stable dimers providing allosteric activation of the receptor. Moreover, receptor phosphorylation is associated with inhibition of PTP-1B phosphatase. Our data offer a promising paradigm for investigating new aspects of signal transduction mediated by EGFR in cancer cells exposed to electrophilic NBD compounds.


Assuntos
Ativação Enzimática/efeitos dos fármacos , Receptores ErbB/metabolismo , Neoplasias/patologia , Nitrocompostos/farmacologia , Oxidiazóis/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Humanos , Fosforilação/efeitos dos fármacos , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tirfostinas/farmacologia
14.
Eur J Med Chem ; 69: 823-32, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24121233

RESUMO

A novel series of 3-methyl-1-benzofuran derivatives were synthesized and screened in vitro for their antiproliferative activity against two human NSCLC cell lines (NSCLC-N6 mutant p53 and A549 wild type p53). Most promising compounds presented a structural analogy with the west part of cercosporamide, a natural product of biological interest. In particular, compounds 10, 12 and 31 showed cytotoxic activities at micromolar concentrations (IC50 < 9.3 µM) and compounds 13, 18 and 32 displayed moderate IC50 values (25-40 µM).


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzofuranos/síntese química , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Estrutura Molecular , Relação Estrutura-Atividade
15.
Mar Drugs ; 11(4): 1304-15, 2013 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-23595058

RESUMO

The marine sponge, Axinyssa djiferi, collected on mangrove tree roots in Senegal, was investigated for glycolipids. A mixture containing new glycosphingolipids, named axidjiferoside-A, -B and -C, accounted for 0.07% of sponge biomass (dry weight) and for 2.16% of total lipids. It showed a significant antimalarial activity, with a 50% inhibitory concentration (IC50) of 0.53 ± 0.2 µM against a chloroquine-resistant strain of Plasmodium falciparum. They were identified as homologous ß-galactopyranosylceramides composed of 2-amino-(6E)-octadec-6-en-1,3,4-triol, and the major one, axidjiferoside-A (around 60%), contained 2-hydroxytetracosanoic acid. Cytotoxicity was studied in vitro on human cancer cell lines (multiple myeloma, colorectal adenocarcinoma, glioblastoma and two lung cancer NSCLC-N6 and A549). Results of this investigation showed that axidjiferosides are of interest, because they proved a good antiplasmodial activity, with only a low cytotoxicity against various human cell lines and no significant antitrypanosomal and antileishmanial activity. Thus, it seems that galactosylceramides with a ß anomeric configuration may be suitable in searching for new antimalarial drugs.


Assuntos
Antimaláricos/farmacologia , Glicoesfingolipídeos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Poríferos/química , Animais , Antimaláricos/administração & dosagem , Antimaláricos/isolamento & purificação , Linhagem Celular Tumoral , Ceramidas/administração & dosagem , Ceramidas/isolamento & purificação , Ceramidas/farmacologia , Cloroquina/farmacologia , Resistência a Medicamentos , Feminino , Galactosilceramidas/administração & dosagem , Galactosilceramidas/isolamento & purificação , Galactosilceramidas/farmacologia , Glicoesfingolipídeos/administração & dosagem , Glicoesfingolipídeos/isolamento & purificação , Humanos , Concentração Inibidora 50 , Camundongos , Monossacarídeos/administração & dosagem , Monossacarídeos/isolamento & purificação , Monossacarídeos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Senegal
16.
Gene ; 506(2): 355-9, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22732573

RESUMO

Lung cancer is a serious public health problem and Non Small Cell Lung Carcinoma, NSCLC, is particularly resistant to current treatments. So it is important to find new strategies that are active against NSCLC. miRNA is implicated in cancer and may be implicated in NSCLC. Our team has been working on two genes HEF1, a gene implicated in different functions of cell cycle and B2, a large non-coding RNA (nc RNA). These two genes have the same localisation: chromosome 6 and locus p24-25. nc RNA B2 may be involved in the regulation of HEF1. Firstly, we examine a bank of different human miRNAs known to interact with exons of HEF1. HEF1 and B2 were overexpressed in vitro by treating NSCLC-N6 with the cytostatic molecule A190, and carried out qRT-PCR for the expression of miRNA. Secondly, using specific software, we sought for structures originating from the B2 RNA sequence which might interact with HEF1 and assessed their expression. This strategy enabled us to confirm firstly that known miRNAs that can interact with exons of HEF1 are expressed in NSCLC-N6 cells. More precisely this strategy highlighted overexpression of one miRNA, hsa-miR-146b, listed in miRbase. The second step of the studies highlighted the expression of miRNA, potentially sequences originating from B2 in the NSCLC-N6. This miRNA overexpressed might be one of the regulators of the gene HEF1 and consequently implies on the carcinogenesis of lung cancer. So in the future it could be a potential and an innovative way to find a new strategy for the treatment of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Ciclo Celular , Linhagem Celular Tumoral , Desoxirribonucleases/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/terapia , MicroRNAs/biossíntese , Fosfoproteínas/genética , RNA não Traduzido/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos
17.
Eur J Med Chem ; 49: 406-10, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22309916

RESUMO

Glycolipids of Myrmekioderma sponges contain Myrmekiosides, a new family of glycolipids with a unique structure of mono-O-alkyl-diglycosylglycerols. This report deals with the identification and biological activity of the new Myrmekioside E from Myrmekioderma dendyi. Its structure has been elucidated from spectroscopic data and chemical degradation studies. It contained a glycerol backbone linked to xylose and N-acetylglucosamine, and an alkyl long-chain with a terminal alcohol group. A related glycolipid, Trikentroside, known in the sponge Trikentrion laeve, was subjected to a comparative biological evaluation. Both glycolipids inhibit proliferation of two human non-small cell lung cancer cell lines (NSCLC-N6 and A549).


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glicolipídeos/química , Glicolipídeos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Poríferos/química , Animais , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glicolipídeos/isolamento & purificação , Humanos
18.
J Ocul Pharmacol Ther ; 28(3): 299-306, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22235844

RESUMO

A cataract is a clouded area of the eye, which impairs vision. Cataracts can be caused by a natural hardening of the lens in the elderly, or may be the result of eye injury. However there is a treatment by extracapsular surgery, almost 50% of operations are followed by another posterior capsule opacification. This secondary cataract is due to abnormal cellular proliferation. Pharmacologic inhibition of this cellular proliferation would be a very promising treatment. The objective of our study is to test some antiproliferative drugs, less toxic than those currently used such as 5-FU or mytomycin C. We have investigated the in vitro effects of several molecules (V0 and its derivatives) on a proliferative human lens epithelial cell line (SRA 01/04). During a first step, we have measured the IC50 of each molecule. After this first screening, we have studied the kinetic of the cell growth with or without the molecules at different concentration. Then, flow cytometry was used to determine the phase of the cell cycle at which the proliferation stopped. This study has shown that 3 molecules V19, V1, and A190 have an interesting profile in vitro and were selected to analyze their mechanism of action.


Assuntos
Catarata/tratamento farmacológico , Cristalino/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Humanos , Cristalino/citologia
19.
Int J Mol Med ; 25(6): 897-903, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20428794

RESUMO

The non-coding RNAs are new players in cellular and molecular biology. Indeed, quantitative and functional non-coding RNA has long been underestimated. There is a great diversity and it seems that much of the genome is transcribed into RNA, while only 1.2% of DNA information is translated into proteins. Non-coding RNA has been categorized according to different specifications so large non-coding RNA includes RNA with 300 to more than 10,000 bp. In this study, we propose a new non-coding RNA named B2 discovered by differential display. B2 is a nuclear RNA which is 51,011 bp long with no significant open reading frame. This RNA has a continuous homology with the genomic DNA of the HEF1/ NEDD9/Cas-L gene located on 6p24-p25. This homology has enabled us to characterize its structure by choosing overlapping fragments to perform several RT-PCRs. B2 RNA extends from 10 kb upstream of exon 1 of the HEF1 gene on the 5' end to exon 4 HEF1 on the 3' end. In addition, a strategic choice of PCR primers enabled us to determine the location of B2 in the subcellular compartment and then real-time PCR revealed overexpression of B2 and HEF1 in certain tissues such as thymus, cervix, liver, and spleen (among the 20 tissues analysed). B2 seems especially interesting in that it can regulate apoptosis and cell proliferation by modulating HEF1. In addition, the fact that cytostatic treatments can induce B2 reinforces the interest in this new potential target in the development of anticancer treatments. These results show that this novel non-coding RNA is an attractive target.


Assuntos
RNA não Traduzido/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Pareamento de Bases/genética , Linhagem Celular Tumoral , Núcleo Celular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Eur J Med Chem ; 45(7): 2912-8, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20381215

RESUMO

The novelty of this work derives from the use of nitrogenous heterocycles as building block in the synthesis of conjugate bile acid derivatives. New piperazinyl bile acid derivatives were synthesized and tested in vitro against various human cancer cells (GBM, KMS-11, HCT-116). The best pro-apoptotic activity was obtained with N-[4N-cinnamylpiperazin-1-yl)-3alpha,7beta-dihydroxy-5beta-cholan-24-amide (7b) and N-[4N-cinnamyllpiperazin-1-yl)- 3alpha,7alpha-dihydroxy-5beta-cholan-24-amide (7c) on these human cancer cell lines (IC(50): 8.5-31.4microM). This activity was associated with nuclear and DNA fragmentation, demonstrating that 7b induces cell death by an apoptotic process as 7c. This study shows the possibility of hydrid heterocycle-steroids as new anticancer agents with improved bioactivity and easy to synthesize.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/síntese química , Ácidos e Sais Biliares/farmacologia , Neoplasias do Colo/patologia , Glioblastoma/patologia , Mieloma Múltiplo/patologia , Ácidos e Sais Biliares/química , Linhagem Celular Tumoral , Humanos , Piperazina , Piperazinas/química
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