Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Int J Cancer ; 142(1): 176-190, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28884474

RESUMO

Cancer cell stress induced by cytotoxic agents promotes antitumor immune response. Here, we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of natural killer (NK) cell activating receptor NK Group 2 member D (NKG2D) ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1 µM) control the selective upregulation of UL16-binding protein 2 on p53wt-expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for NK cell-mediated recognition through a NKG2D restricted mechanism. p53 siRNA-mediated knock-down and pharmacological inhibition (pifithrin-α), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest. Collectively, our results indicate that behind the well established cytotoxic and antiangiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in antiglioma research.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Glioma/patologia , Isopenteniladenosina/farmacologia , Células Matadoras Naturais/patologia , Animais , Antineoplásicos/imunologia , Neoplasias Encefálicas/imunologia , Linhagem Celular Tumoral , Glioma/imunologia , Humanos , Isopenteniladenosina/imunologia , Células Matadoras Naturais/imunologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Pharmacol Res ; 88: 84-98, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25009097

RESUMO

Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed toward the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Ácido Mevalônico/antagonistas & inibidores , Ácido Mevalônico/metabolismo , Neoplasias/metabolismo , Neoplasias/prevenção & controle
3.
Malar J ; 13: 510, 2014 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-25526742

RESUMO

BACKGROUND: Two long synthetic peptides representing the dimorphic and constant C-terminal domains of the two allelic families of Plasmodium falciparum merozoite surface proteins 2 are considered promising malaria vaccine candidates. The aim of the current study is to characterize the immune response (epitope mapping) in naturally exposed individuals and relate immune responses to the risk of clinical malaria. METHODS: To optimize their construction, the fine specificity of human serum antibodies from donors of different age, sex and living in four distinct endemic regions was determined in ELISA by using overlapping 20 mer peptides covering the two domains. Immune purified antibodies were used in Western blot and immunofluorescence assay to recognize native parasite derivate proteins. RESULTS: Immunodominant epitopes were characterized, and their distribution was similar irrespective of geographic origin, age group and gender. Acquisition of a 3D7 family and constant region-specific immune response and antibody avidity maturation occur early in life while a longer period is needed for the corresponding FC27 family response. In addition, the antibody response to individual epitopes within the 3D7 family-specific region contributes to protection from malaria infection with different statistical weight. It is also illustrated that affinity-purified antibodies against the dimorphic or constant regions recognized homologous and heterologous parasites in immunofluorescence and homologous and heterologous MSP2 and other polypeptides in Western blot. CONCLUSION: Data from this current study may contribute to a development of MSP2 vaccine candidates based on conserved and dimorphic regions thus bypassing the complexity of vaccine development related to the polymorphism of full-length MSP2.


Assuntos
Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Mapeamento de Epitopos , Epitopos/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Western Blotting , Criança , Pré-Escolar , Sequência Conservada/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Imunofluorescência , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Pharmacol Res ; 65(3): 365-71, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22123497

RESUMO

Emerging findings suggested the efficacy of the cannabinoid CB1 receptor antagonist rimonabant (SR141716) in several pathological conditions included tumours. In this study we investigated in vitro the effects of SR141716 on viability and the molecular pathways of methylcholanthrene-induced fibrosarcoma (Meth-A) cells and in vivo its anti-tumour properties in Meth-A-bearing mice. We evaluated in vitro the effect of SR141716 on Meth-A cell viability by trypan blue staining assay. Cell cycle progression and apoptosis were assessed by flow cytometry. Protein expression was investigated by Western blot. The anti-tumour efficacy of SR141716 was evaluated in vivo monitoring weight increase and survival of Meth-A injected mice. SR141716 affects Meth-A cell viability inducing apoptosis and controls cell cycle progression by modulation of the levels of the cell cycle inhibitor p21waf, cyclins E, D1 and NF-kB molecules. Importantly, SR141716 affects AKT/pFoxO1 pathway which promotes cell survival and regulates the cell cycle. The molecular effects observed are accompanied by reduced COX2 expression and induction of the CB1 receptor expression. Finally, SR141716 was able to reduce the tumour size and prolong animal survival, when administered in vivo during tumour growth. Our findings shed light on a novel molecular pathway associated with control of tumour growth by SR141716 and confirm the anti-cancer and anti-inflammatory properties of this drug suggesting its potential applications in the treatment of cancer.


Assuntos
Antineoplásicos/uso terapêutico , Ascite/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fibrossarcoma/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Piperidinas/farmacologia , Pirazóis/farmacologia , Rimonabanto
5.
Xenotransplantation ; 17(6): 431-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21158944

RESUMO

BACKGROUND: Clinical use of porcine cell-based bioartificial liver (BAL) support in acute liver failure as bridging therapy for liver transplantation exposes the patient to the risk of transmission of porcine endogenous retroviruses (PERVs) to human. This risk may be enhanced when patients receive liver transplant and are subsequently immunosuppressed. As further follow-up of previously reported patients (Di Nicuolo et al. 2005), an assessment of PERV infection was made in the same patient population pharmacologically immunosuppressed for several years after BAL treatment and in healthcare workers (HCWs) involved in the clinical trial at that time. METHODS: Plasma and peripheral blood mononuclear cells (PBMCs) from eight patients treated with the Academic Medical Center-BAL (AMC-BAL), who survived to transplant, and 13 HCWs, who were involved in the trial, were assessed to detect PERV infection. A novel quantitative real-time polymerase chain reaction assay has been used. RESULTS: Eight patients who received a liver transplant after AMC-BAL treatment are still alive under long-term pharmacological immunosuppression. The current clinical follow-up ranges from 5.6 to 8.7 yr after BAL treatment. A new q-real-time PCR assay has been developed and validated to detect PERV infection. The limit of quantification of PERV DNA was ≥ 5 copies per 1 × 10(5) PBMCs. The linear dynamic range was from 5 × 10(0) to 5 × 10(6) copies. In both patients and HCWs, neither PERV DNA in PBMCs nor PERV RNA in plasma and PBMC samples have been found. CONCLUSION: Up to 8.7 yr after exposure to treatment with porcine liver cell-based BAL, no PERV infection has been found in long-term immunosuppressed patients and in HCWs by a new highly sensitive and specific q-real-time PCR assay.


Assuntos
Retrovirus Endógenos/patogenicidade , Hospedeiro Imunocomprometido , Fígado Artificial/virologia , Infecções por Retroviridae/etiologia , Transplante Heterólogo/efeitos adversos , Animais , DNA Viral/sangue , Retrovirus Endógenos/genética , Humanos , Imunossupressores/uso terapêutico , Transplante de Fígado/efeitos adversos , Transplante de Fígado/imunologia , Suínos , Transplante Heterólogo/imunologia
6.
Oncotarget ; 6(17): 15464-81, 2015 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-26008966

RESUMO

Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-ß1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.


Assuntos
Apoptose/efeitos dos fármacos , Glioma/tratamento farmacológico , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Astrócitos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glioma/imunologia , Glioma/patologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Nus , Interferência de RNA , RNA Interferente Pequeno , Receptor CB1 de Canabinoide/biossíntese , Receptor CB1 de Canabinoide/genética , Rimonabanto , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Trends Pharmacol Sci ; 34(5): 273-82, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23602129

RESUMO

Changes in lipid metabolism are intimately related to cancer. Several classes of bioactive lipids play roles in the regulation of signaling pathways involved in neoplastic transformation and tumor growth and progression. The endocannabinoid system, comprising lipid-derived endocannabinoids, their G-protein-coupled receptors (GPCRs), and the enzymes for their metabolism, is emerging as a promising therapeutic target in cancer. This report highlights the main signaling pathways for the antitumor effects of the endocannabinoid system in cancer and its basic role in cancer pathogenesis, and discusses the alternative view of cannabinoid receptors as tumor promoters. We focus on new players in the antitumor action of the endocannabinoid system and on emerging crosstalk among cannabinoid receptors and other membrane or nuclear receptors involved in cancer. We also discuss the enzyme MAGL, a key player in endocannabinoid metabolism that was recently recognized as a marker of tumor lipogenic phenotype.


Assuntos
Endocanabinoides/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Transdução de Sinais
8.
FEBS J ; 280(23): 6223-32, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24112551

RESUMO

Hutchinson-Gilford progeria syndrome is caused by mutations in the lamin A/C gene that lead to expression of a truncated, permanently farnesylated prelamin A variant called progerin. The accumulation of progerin at the nuclear envelope causes mis-shapen nuclei and results in progeroid syndromes. Previous studies in cells from individuals with Hutchinson-Gilford progeria syndrome have shown that blocking of farnesylation of prelamin A ameliorates the nuclear shape abnormalities. Here we observed that an inhibitor of farnesyl diphosphate synthase, N6-isopentenyladenosine, impeded the farnesylation of prelamin A, causing a decrease in the frequency of nuclear shape abnormalities and redistribution of prelamin A away from the inner nuclear envelope. A combination of lovastatin and N6-isopentenyladenosine significantly improved nuclear shape in fibroblast cell lines from atypical progeria patients. These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes, and suggest a potential strategy for treating children with Hutchinson-Gilford progeria syndrome.


Assuntos
Núcleo Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Isopenteniladenosina/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Reguladores de Crescimento de Plantas/farmacologia , Progéria/tratamento farmacológico , Precursores de Proteínas/antagonistas & inibidores , Prenilação de Proteína/efeitos dos fármacos , Adolescente , Adulto , Western Blotting , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Células Cultivadas , Criança , Fibroblastos/metabolismo , Fibroblastos/patologia , Geraniltranstransferase/metabolismo , Humanos , Imunoprecipitação , Lamina Tipo A , Masculino , Microscopia de Fluorescência , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Progéria/metabolismo , Progéria/patologia , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
J Leukoc Biol ; 94(6): 1207-19, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23847096

RESUMO

iPA is a naturally occurring nucleoside with an isopentenyl moiety derived from the mevalonate pathway and a well-established anti-tumor activity. In analogy to the unique specificity for phosphoantigens, such as IPP, shown by human Vγ9Vδ2 T cells, here, we report for the first time the ability of iPA to selectively expand and directly target human NK cells. Interestingly, submicromolar doses of iPA stimulate resting human NK cells and synergize with IL-2 to induce a robust activation ex vivo with significant secretion of CCL5 and CCL3 and a large increase in TNF-α and IFN-γ production when compared with IL-2 single cytokine treatment. Moreover, iPA promotes NK cell proliferation and up-regulates the expression of specific NK cell-activating receptors, as well as CD69 and CD107a expression. Accordingly, this phenotype correlates with significantly greater cytotoxicity against tumor targets. At the molecular level, iPA leads to a selective, potent activation of MAPK signaling intermediaries downstream of the IL-2R. The effect results, at least in part, from the fine modulation of the FDPS activity, the same enzyme implicated in the stimulation of the human γδ T cells. The iPA-driven modulation of FDPS can cause an enhancement of post-translational prenylation essential for the biological activity of key proteins in NK signaling and effector functions, such as Ras. These unanticipated properties of iPA provide an additional piece of evidence of the immunoregulatory role of the intermediates of the mevalonate pathway and open novel therapeutic perspectives for this molecule as an immune-modulatory drug.


Assuntos
Geraniltranstransferase/imunologia , Imunidade Celular/fisiologia , Isopenteniladenosina/imunologia , Células Matadoras Naturais/imunologia , Sistema de Sinalização das MAP Quinases/fisiologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Quimiocina CCL3/biossíntese , Quimiocina CCL3/imunologia , Quimiocina CCL5/biossíntese , Quimiocina CCL5/imunologia , Feminino , Regulação da Expressão Gênica/fisiologia , Geraniltranstransferase/metabolismo , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-2/imunologia , Isopenteniladenosina/metabolismo , Isopenteniladenosina/farmacologia , Células K562 , Células Matadoras Naturais/citologia , Células Matadoras Naturais/enzimologia , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Reguladores de Crescimento de Plantas/imunologia , Reguladores de Crescimento de Plantas/farmacologia , Prenilação de Proteína/fisiologia , Receptores de Antígenos de Linfócitos T gama-delta , Terpenos/imunologia , Terpenos/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
10.
PLoS One ; 8(5): e62511, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23658734

RESUMO

The efficacy of cannabinoids in the treatment of multiple sclerosis is widely documented; however their use is limited by psychoactivity mainly ascribed to the activation of the cannabinoid receptor CB1. Emerging findings support as alternative strategy in the treatment of neurodegenerative disorders, the application of compounds targeting the CB2 receptor, since likely unrelated to these side effects. Recently, a novel class of compounds, 1,8-naphthyridine, pyridine and quinoline derivatives have been demonstrated to show high CB2 receptor selectivity and affinity versus the CB1 receptor. Considering that the CB2 receptor is mainly expressed in cell and organs of the immune system, in this study we assessed the potential immune-modulatory effects of these compounds in activated lymphocytes isolated from MS patients with respect to healthy controls. These compounds blocked cell proliferation through a mechanism partially ascribed to the CB2 receptor, down-regulated TNF-α production and did not induce cell death. They also down-regulated Akt, Erk and NF-kB phosphorylation. Despite comparable effects observed in patients and healthy controls, these compounds, in particular, 1,8-naphthyridine and quinoline derivatives inhibited cell activation markers in MS patient derived lymphocytes more efficiently than in healthy control derived cells. Indeed, 1,8-naphthyridin-2-one derivative reduced the levels of Cox-2 in lymphocytes from patients whereas no effect was observed in control cells. Our findings suggest potential application of these drugs in neuro-inflammation, supporting further investigations of the effects of compounds in the therapy of MS, particularly on the aspects regarding activation and inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Esclerose Múltipla/tratamento farmacológico , Naftiridinas/farmacologia , Piridonas/farmacologia , Quinolonas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Expressão Gênica , Humanos , Imunossupressores/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Lectinas Tipo C/metabolismo , Ativação Linfocitária , Esclerose Múltipla/imunologia , Proteína Básica da Mielina/fisiologia , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
11.
Eur J Cancer ; 48(16): 3112-22, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22425263

RESUMO

We previously showed that methyl-F-anandamide, a stable analogue of the anandamide, inhibited the growth and the progression of cultured human breast cancer cells. As accumulating evidences indicate that the constitutive activation of the canonical Wnt pathway in human breast cancer may highlight a key role for aberrant activation of the ß-catenin-TCF cascade and tumour progression, we studied the anandamide effect on the key elements of Wnt pathway in breast cancer cells. In this study we described that the treatment of human breast cancer cells, MDA MB 231 cells, with methyl-F-anandamide reduced protein levels of ß-catenin in the cytoplasmic and nuclear fractions inhibiting the transcriptional activation of T Cell Factor (TCF) responsive element (marker for ß-catenin signalling). The anandamide treatment resulted in up-regulation of epithelial markers, like E-cadherin with a concomitant decrease in protein levels of mesenchymal markers, including vimentin and Snail1. We, furthermore, observed that the induction of experimental epithelial-mesenchymal transition by exposure to adriamycin in MCF7 human breast cancer cell line was inhibited by anandamide treatment. In the present study we reported a novel anticancer effect of anandamide involving the inhibition of epithelial-mesenchymal transition, a process triggered during progression of cancer to invasive state.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular , Antibióticos Antineoplásicos/farmacologia , Antígenos CD , Biomarcadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Caderinas/metabolismo , Doxorrubicina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Genes Reporter , Humanos , Células MCF-7 , Regiões Promotoras Genéticas , Estabilidade Proteica , Fatores de Transcrição TCF/genética , Fatores de Transcrição TCF/metabolismo , Fatores de Tempo , Transfecção , beta Catenina/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA