RESUMO
BACKGROUND: Over the past decade, newly designed cancer therapies have not significantly improved the survival of patients diagnosed with Malignant Pleural Mesothelioma (MPM). Among a limited number of genes that are frequently mutated in MPM several of them encode proteins that belong to the HIPPO tumor suppressor pathway. METHODS: The anticancer effects of the top flower standardized extract of Filipendula vulgaris (Dropwort) were characterized in "in vitro" and "in vivo" models of MPM. At the molecular level, two "omic" approaches were used to investigate Dropwort anticancer mechanism of action: a metabolomic profiling and a phosphoarray analysis. RESULTS: We found that Dropwort significantly reduced cell proliferation, viability, migration and in vivo tumor growth of MPM cell lines. Notably, Dropwort affected viability of tumor-initiating MPM cells and synergized with Cisplatin and Pemetrexed in vitro. Metabolomic profiling revealed that Dropwort treatment affected both glycolysis/tricarboxylic acid cycle as for the decreased consumption of glucose, pyruvate, succinate and acetate, and the lipid metabolism. We also document that Dropwort exerted its anticancer effects, at least partially, promoting YAP and TAZ protein ubiquitination. CONCLUSIONS: Our findings reveal that Dropwort is a promising source of natural compound(s) for targeting the HIPPO pathway with chemo-preventive and anticancer implications for MPM management.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Metabolismo Energético/efeitos dos fármacos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Mesotelioma/etiologia , Mesotelioma/metabolismo , Extratos Vegetais/farmacologia , Fatores de Transcrição/metabolismo , Aciltransferases , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Filipendula/química , Humanos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Extratos Vegetais/química , Ligação ProteicaRESUMO
The impact of gender and diet on the proteome of Longissimus dorsi was addressed by 2D-PAGE analysis of male and female pigs, fed with a barley-based control diet and a diet enriched with extruded linseed and plant extracts. No statistically significant difference in protein number between female and male samples was found. Furthermore, PCA excluded gender-dependent protein clusters. For both the control and enriched diet, several spots exhibited at least a 1.5-fold intensity difference, but none showed a statistically relevant variation. Protein profiles PCA for both diets indicated that the first two principal components account up to 47% of total variance, with two diet-dependent separated clusters. Among 176 common spots, 29 exhibited >1.5 fold change, mostly more abundant in the control diet. PMF identified 14 distinct proteins, including myofibrillar proteins, glycolytic enzymes and myoglobin, thus suggesting a diet-dependent meat quality. A statistically significant increase in carbonylated proteins of enriched diet samples was detected using the 2,4-dinitrophenylhydrazine method but not using fluorescein-5-thiosemicarbazide-labeled bands. ROS induction and DNA oxidative damage, detected in a human cell line exposed to digested meat from both diets, further support the notion that the enriched diet does not protect against oxidative stress. SIGNIFICANCE: The comparison of the protein profile of female and male Longissimus dorsi from pigs fed by a control diet and a diet enriched with polyphenols, indicate no gender effect, whereas diet affects the abundance of several proteins, possibly linked to meat quality. Protein carbonylation was statistically higher in meat from the enriched diet, suggesting that polyphenols at the concentration present in the diet did not exert a protective effect against oxidation.
Assuntos
Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Proteínas Alimentares/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Suínos , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Dieta , Suplementos Nutricionais , Ácidos Graxos/metabolismo , Feminino , Linho/química , Linho/fisiologia , Masculino , Metaboloma/efeitos dos fármacos , Músculo Esquelético/química , Oxirredução/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Caracteres Sexuais , Suínos/metabolismoRESUMO
Malignant pleural mesothelioma is a poorly treated neoplasia arising from the pleural mesothelial lining. Here we document that the leaf extract of Cynara scolymus exerts broad antitumoral effects both in vitro and in vivo on mesothelioma cell lines. We found that Cynara scolymus treatment affects strongly cell growth, migration and tumor engraftment of mesothelioma cell lines. Strikingly, dietary feeding with Cynara scolymus leaf extract reduces the growth of mesothelioma xenografted tumors similarly to pemetrexed, a commonly employed drug in the treatment of mesothelioma. In aggregate our findings suggest that leaf extract of Cynara scolymus holds therapeutic potential for the treatment of mesothelioma.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Cynara scolymus , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Extratos Vegetais/farmacologia , Neoplasias Pleurais/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cynara scolymus/química , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mesotelioma/metabolismo , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Invasividade Neoplásica , Fitoterapia , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Plantas Medicinais , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Dietary agents are receiving much attention for the chemoprevention of cancer. While curcumin is known to influence several pathways and affect tumor growth in vivo, carnitin and its congeners play a variety of important metabolic functions: are involved in the oxydation of long-chain fatty acids, regulate acyl-CoA levels and influence protein activity and stability by modifying the extent of protein acetylation. In this study we evaluated the efficacy of carnitines in the prevention of cancer development using the 1,2,-dimethylhydrazine (DMH)-induced colon carcinogenesis model. We also assessed whether their combination was able to give rise to increased protection from cancer development. Mice treated with DMH were dosed orally with curcumin and/or carnitine and acylcarnitines for 20 weeks. At the end of the treatment colon samples were collected, and scored for multiple ACF and adenomas. We observed that carnitine and acyl-carnitines had same, if not higher, efficacy than curcumin alone in inhibiting the formation of neoplastic lesions induced by DMH treatment. Interestingly, the combination of curcumin and acetyl-L-carnitine was able to fully inhibit the development of advanced adenoma lesions. Our data unveil the antitumor effects of carnitines and warrant additional studies to further support the adoption of carnitines as cancer chemopreventative agents.