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4.
Oncogene ; 35(29): 3839-53, 2016 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-26640148

RESUMO

A limiting factor in the therapeutic outcome of children with high-risk neuroblastoma is the intrinsic and acquired resistance to common chemotherapeutic treatments. Here we investigated the molecular mechanisms by which the hemisynthetic cardiac glycoside UNBS1450 overcomes this limitation and induces differential cell death modalities in both neuroblastic and stromal neuroblastoma through stimulation of a cell-type-specific autophagic response eventually leading to apoptosis or necroptosis. In neuroblastic SH-SY5Y cells, we observed a time-dependent production of reactive oxygen species that affects lysosomal integrity inducing lysosome-associated membrane protein 2 degradation and cathepsin B and L activation. Subsequent mitochondrial membrane depolarization and accumulation of mitochondria in phagophores occurred after 8h of UNBS1450 treatment. Results were confirmed by mitochondrial mass analysis, electron microscopy and co-localization of mitochondria with GFP-LC3, suggesting the impaired clearance of damaged mitochondria. Thus, a stress-induced defective autophagic flux and the subsequent lack of clearance of damaged mitochondria sensitized SH-SY5Y cells to UNBS1450-induced apoptosis. Inhibition of autophagy with small inhibitory RNAs against ATG5, ATG7 and Beclin-1 protected SH-SY5Y cells against the cytotoxic effect of UNBS1450 by inhibiting apoptosis. In contrast, autophagy progression towards the catabolic state was observed in stromal SK-N-AS cells: here reactive oxygen species (ROS) generation remained undetectable preserving intact lysosomes and engulfing damaged mitochondria after UNBS1450 treatment. Moreover, autophagy inhibition determined sensitization of SK-N-AS to apoptosis. We identified efficient mitophagy as the key mechanism leading to failure of activation of the apoptotic pathway that increased resistance of SK-N-AS to UNBS1450, triggering rather necroptosis at higher doses. Altogether we characterize here the differential modulation of ROS and mitophagy as a main determinant of neuroblastoma resistance with potential relevance for personalized anticancer therapeutic approaches.


Assuntos
Apoptose/genética , Regulação Neoplásica da Expressão Gênica/genética , Mitofagia/genética , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/genética , Western Blotting , Cardenolídeos/farmacologia , Catepsina B/metabolismo , Catepsina L/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Mitofagia/efeitos dos fármacos , Necrose , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/ultraestrutura , Células U937
5.
Cell Death Dis ; 6: e1782, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-26068790

RESUMO

Cardiac glycosides (CGs), prescribed to treat cardiovascular alterations, display potent anti-cancer activities. Despite their well-established target, the sodium/potassium (Na(+)/K(+))-ATPase, downstream mechanisms remain poorly elucidated. UNBS1450 is a hemi-synthetic cardenolide derived from 2″-oxovorusharin extracted from the plant Calotropis procera, which is effective against various cancer cell types with an excellent differential toxicity. By comparing adherent and non-adherent cancer cell types, we validated Mcl-1 as a general and early target of UNBS1450. A panel of CGs including cardenolides ouabain, digitoxin and digoxin as well as bufadienolides cinobufagin and proscillaridin A allowed us to generalize our findings. Our results show that Mcl-1, but not Bcl-xL nor Bcl-2, is rapidly downregulated prior to induction of apoptosis. From a mechanistic point of view, we exclude an effect on transcription and demonstrate involvement of a pathway affecting protein stability and requiring the proteasome in the early CG-induced Mcl-1 downregulation, without the involvement of caspases or the BH3-only protein NOXA. Strategies aiming at preventing UNBS1450-induced Mcl-1 downregulation by overexpression of a mutated, non-ubiquitinable form of the protein or the use of the proteasome inhibitor MG132 inhibited the compound's ability to induce apoptosis. Altogether our results point at Mcl-1 as a ubiquitous factor, downregulated by CGs, whose modulation is essential to achieve cell death.


Assuntos
Antineoplásicos/farmacologia , Apoptose/fisiologia , Cardenolídeos/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Apoptose/efeitos dos fármacos , Calotropis/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Células Jurkat , Leupeptinas/farmacologia , Células MCF-7 , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transcrição Gênica/genética , Proteína bcl-X/metabolismo
7.
Curr Top Med Chem ; 12(13): 1392-407, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22650373

RESUMO

TNF-α was discovered more then 20 years ago as a cytokine implicated in a wide range of cell signaling pathways, many of which are known to lead to the activation of genes involved in inflammation and carcinogenesis. TNF-α is involved in the pathogenesis of many diseases, including Crohn's disease, diabetes, septic shock, tumorigenesis, rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Multidisciplinary research endeavoring to understand the biomolecular and biomedicinal properties of TNF-α has never faded away, and the search for natural products able to inhibit TNF-α remains, to date, a hot topic of investigation. Over the last 10 years, many TNF-α-inhibiting natural compounds have been discovered, and their anti-TNF-α activities have been described. The present review describes the major cell signaling pathways activated by TNF-α and discusses the chemical and biological properties of TNF-α-inhibiting natural products, focusing on compounds that are able to inhibit TNF-α-related signal transduction pathways or TNF-α gene expression.


Assuntos
Produtos Biológicos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Humanos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Ann Oncol ; 23(8): 1986-1992, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22396444

RESUMO

BACKGROUND: While guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) are widely available, clinical uptake of guidelines remains low. Our objective was to evaluate the effect of guideline-consistent CINV prophylaxis (GCCP) on patient outcomes. PATIENTS AND METHODS: This prospective, observational multicenter study enrolled chemotherapy-naive adults initiating single-day highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer. Patients completed 6-day daily diaries beginning with cycle 1 for up to three chemotherapy cycles. The primary study end point, complete response (no emesis and no use of rescue therapy) during 120 h after cycle 1 chemotherapy, was compared between GCCP and guideline-inconsistent CINV prophylaxis (GICP) cohorts using multivariate logistic regression, adjusting for potential confounding factors. RESULTS: In cycle 1 (N=991), use of GCCP was 55% and 46% during acute and delayed phases, respectively, and 29 % for the overall study period (acute plus delayed phases). Complete response was recorded by 172/287 (59.9%) and 357/704 (50.7%) patients in GCCP and GICP cohorts, respectively (P=0.008). The adjusted odds ratio for complete response was 1.43 (95% confidence interval 1.04-1.97; P=0.027) for patients receiving GCCP versus GICP. CONCLUSION: GCCP reduces the incidence of CINV after single-day HEC and MEC.


Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Fidelidade a Diretrizes , Náusea/induzido quimicamente , Náusea/terapia , Vômito/induzido quimicamente , Vômito/terapia , Antineoplásicos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/tratamento farmacológico , Náusea/prevenção & controle , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Vômito/tratamento farmacológico , Vômito/prevenção & controle
10.
Biochem Pharmacol ; 82(10): 1291-303, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21782802

RESUMO

Erythropoietin (EPO) is a glycoprotein that is mainly produced in the adult kidney, and it was initially highlighted for its action on the hematopoietic system. Moreover, EPO is also expressed in several non-hematopoietic tissues, where it plays a role in the protection from apoptosis and inflammation due to hypoxia, toxicity or injury. These protective effects are mainly known and studied in cardioprotection and neuroprotection but are also reported in retina degeneration, auditory injury and pancreatic-related diseases. The tissue protective effect of EPO is mainly mediated through the interaction with the heterodimeric receptor EPOR/ßcR. Human recombinant EPO (HuREPO), which has been developed to treat anemia, is not adequate for tissue protection. The low affinity of the alternative receptor for EPO involves the injection of excessive concentration of erythropoiesis-stimulating agents (ESAs), implicating side effects due to the cross-talk with hematopoietic activity. For these reasons, EPO derivatives with less affinity for the EPO homodimeric receptor are under development. In this review, we provide an overview of the erythroid and non-erythroid functions of EPO by detailing the molecular mechanisms activated by the binding of EPO to its receptors in different tissues.


Assuntos
Eritropoese/efeitos dos fármacos , Eritropoese/fisiologia , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Encéfalo/efeitos dos fármacos , Eritropoetina/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Neovascularização Fisiológica/efeitos dos fármacos
11.
Ann Oncol ; 22 Suppl 5: v1-9, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21633049

RESUMO

Well-recognized experts in the field of gastric cancer discussed during the 12th European Society Medical Oncology (ESMO)/World Congress Gastrointestinal Cancer (WCGIC) in Barcelona many important and controversial topics on the diagnosis and management of patients with gastric cancer. This article summarizes the recommendations and expert opinion on gastric cancer. It discusses and reflects on the regional differences in the incidence and care of gastric cancer, the definition of gastro-esophageal junction and its implication for treatment strategies and presents the latest recommendations in the staging and treatment of primary and metastatic gastric cancer. Recognition is given to the need for larger and well-designed clinical trials to answer many open questions.


Assuntos
Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Predisposição Genética para Doença , Humanos , Metástase Neoplásica , Guias de Prática Clínica como Assunto , Prognóstico , Fatores de Risco , Neoplasias Gástricas/patologia , Taxa de Sobrevida
12.
Artigo em Inglês | MEDLINE | ID: mdl-20882745

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease caused by defective lymphocyte apoptosis and is characterized by non-malignant lymphoproliferation, hepatosplenomegaly, autoimmune manifestations and increased risk of both Hodgkin's and non-Hodgkin's lymphoma. Most forms of the disease are due to germ line mutations of the FAS gene and manifest during the first years of life with fluctuating lymphadenopathies, hemolysis, immune thrombocytopenia. During the second decade of life disease manifestations improve spontaneously but autoimmune problems still occur and there is an increased risk of lymphoproliferative malignancy. We describe a typical case of ALPS in a now 44 year old man, followed since the age of 2 for disease manifestations that were unclear at the beginning.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/classificação , Síndrome Linfoproliferativa Autoimune/genética , Diagnóstico Diferencial , Mutação em Linhagem Germinativa , Humanos , Masculino
13.
Ann Oncol ; 21 Suppl 7: vii167-72, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20943610

RESUMO

Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), among others, play a major role in the pathophysiology of anemia in the cancer patient not only through complex mechanisms of the purely inflammatory situation but also through genetic regulatory aspects of erythropoiesis via GATA-1 and GATA-2, and other factors. In terms of therapy, iron is used more and more; the late side effects of transfusions are not really understood and the recent controversy regarding erythropoietin usage has resulted in regulatory authorities and scientific societies providing several recommendations and guidelines. These various aspects are addressed herein.


Assuntos
Anemia/etiologia , Anemia/terapia , Neoplasias/complicações , Neoplasias/terapia , Anemia/diagnóstico , Anemia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transfusão de Sangue/métodos , Eritropoetina/uso terapêutico , Humanos , Neoplasias/epidemiologia
14.
Ann Oncol ; 21 Suppl 6: vi1-10, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20534623

RESUMO

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Antineoplásicos/efeitos adversos , Biomarcadores/metabolismo , Antígeno Carcinoembrionário/análise , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/antagonistas & inibidores , Humanos , Instabilidade de Microssatélites , Mutação , Metástase Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Espanha , Proteínas ras/genética
15.
Ann Oncol ; 20 Suppl 7: vii1-vii6, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19497945

RESUMO

This article summarizes the expert discussion on the management of hepatocellular carcinoma (HCC), which took place during the 10th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, June 2008. A multidisciplinary approach to a patient with HCC is essential, to guarantee optimal diagnosis and staging, planning of surgical options and selection of embolisation strategies or systemic therapies. In many patients, the underlying cirrhosis represents a challenge and determines therapeutic options. There is now robust evidence in favour of systemic therapy with sorafenib in patients with advanced HCC with preserved liver function. Those involved in the care for patients with HCC should be encouraged to participate in well-designed clinical trials, to increase evidence-based knowledge and to make further progress.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Humanos
16.
Mediators Inflamm ; 2009: 405016, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20204172

RESUMO

Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway, without erythropoietin defect. This suggested that pro-inflammatory cytokine-mediated signaling pathways affect erythropoietin activity. They could interfere with erythropoietin-mediated signaling pathways, inducing early apoptosis and perturbing the expression and regulation of specific transcription factors involved in the control of erythroid differentiation. In this review we summarize the effect of tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL), and interferon (IFN)-gamma on erythropoiesis with a particular interest for molecular feature.


Assuntos
Anemia/etiologia , Citocinas/fisiologia , Eritropoese/fisiologia , Mediadores da Inflamação/fisiologia , Apoptose , Eritropoese/efeitos dos fármacos , Eritropoetina/fisiologia , Humanos , Técnicas In Vitro , Inflamação/sangue , Inflamação/complicações , Interferon gama/fisiologia , Modelos Biológicos , Neoplasias/sangue , Neoplasias/complicações , Estresse Oxidativo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/fisiologia
17.
Biochem Pharmacol ; 76(11): 1533-43, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18765235

RESUMO

Monocytes isolated and cultured according to standard procedures from the blood of 22 healthy donors display an activation process, monitored as adhesion and increased exposure of CD11. Starting from very early time points, monocytes undergo a deep redox modulation, i.e., they increase reactive oxygen species (ROS) formation and decrease glutathione content; at the same time, the anti-apoptotic protein Bcl-2 is substantially up-regulated. The cause-effect relationship between these parameters was investigated. On the one side, pharmacological glutathione depletion with BSO further increases ROS formation and Bcl-2 levels. On the other side, scavenging of ROS by Trolox prevents Bcl-2 up-regulation. Two lipoxygenase (LOX) inhibitors (CAPE or AA861) prevent ROS increase and, accordingly, also prevent Bcl-2 up-regulation. All this evidence supports the redox-sensitivity of Bcl-2 regulation. Trolox, CAPE and AA861, i.e., all treatments that abolish ROS increase and prevent Bcl-2 up-regulation, increase the rate of cell loss, whereas BSO, increasing Bcl-2, reduces cell loss and induces chemo-resistance. Thus, explanted healthy monocytes seem to undergo an oxidation-dependent maturation implying increased survival via Bcl-2 up-regulation, perhaps mimicking physiological activation.


Assuntos
Sobrevivência Celular , Monócitos/citologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Regulação para Cima , Adulto , Apoptose , Diferenciação Celular , Proliferação de Células , Feminino , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Glutationa/metabolismo , Humanos , Masculino , Oxirredução , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Ann Oncol ; 19 Suppl 6: vi1-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18539618

RESUMO

Knowledge of the biology and management of rectal cancer continues to improve. A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is mandatory, to assure optimal diagnosis and staging, surgery, selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management. Moreover, optimal symptom management also requires a dedicated team of health care professionals. The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery. High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control. There are now randomized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting. Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy. Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer. New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority. Those involved in the care for patients with rectal cancer should be encouraged to participate in well-designed clinical trials, to increase the evidence-based knowledge and to make further progress. Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise.


Assuntos
Neoplasias Retais/diagnóstico , Neoplasias Retais/terapia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Terapia Neoadjuvante , Metástase Neoplásica/terapia , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Cuidados Pré-Operatórios/métodos , Controle de Qualidade , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Retais/patologia
20.
Ann Oncol ; 18 Suppl 7: vii1-vii10, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17600091

RESUMO

This article summarizes the expert discussion on the management of pancreatic cancer, which took place during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery, selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover, optimal symptomatic management requires a dedicated team of health care professionals. Quality control of surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the evidence-based knowledge and to make further progress.


Assuntos
Neoplasias Pancreáticas/terapia , Terapia Combinada , Humanos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/diagnóstico
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