ABSTRACT
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.
Subject(s)
Cell Cycle Proteins/metabolism , Energy Metabolism/drug effects , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Mesothelioma/etiology , Mesothelioma/metabolism , Plant Extracts/pharmacology , Transcription Factors/metabolism , Acyltransferases , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Filipendula/chemistry , Humans , Lung Neoplasms/pathology , Mesothelioma/pathology , Mesothelioma, Malignant , Mice , Plant Extracts/chemistry , Protein BindingABSTRACT
Osteosarcoma (OS) is the most aggressive type of primary solid tumor that develops in bone. Whilst conventional chemotherapy can improve survival rates, the outcome for patients with metastatic or recurrent OS remains poor, so novel treatment agents and strategies are required. Research into new anticancer therapies has paved the way for the utilisation of natural compounds as they are typically less expensive and less toxic compared to conventional chemotherapeutics. Previously published works indicate that Agave exhibits anticancer properties, however potential molecular mechanisms remain poorly understood. In the present study, we investigate the anticancer effects of Agave leaf extract in OS cells suggesting that Agave inhibits cell viability, colony formation, and cell migration, and can induce apoptosis in OS cell lines. Moreover, Agave sensitizes OS cells to cisplatin (CDDP) and radiation, to overcome chemo- and radio-resistance. We demonstrate that Agave extract induces a marked decrease of Yes Associated Protein (YAP) and Tafazzin (TAZ) mRNA and protein expression upon treatment. We propose an initial mechanism of action in which Agave induces YAP/TAZ protein degradation, followed by a secondary event whereby Agave inhibits YAP/TAZ transcription, effectively deregulating the Nuclear Factor kappa B (NF-κB) p65:p50 heterodimers responsible for transcriptional induction of YAP and TAZ.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Agave/chemistry , Bone Neoplasms/metabolism , Osteosarcoma/metabolism , Phosphoproteins/metabolism , Plant Extracts/pharmacology , Transcription Factors/metabolism , Acyltransferases , Adaptor Proteins, Signal Transducing/genetics , Bone Neoplasms/drug therapy , Bone Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cisplatin/pharmacology , Down-Regulation , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Osteosarcoma/drug therapy , Osteosarcoma/genetics , Phosphoproteins/genetics , Plant Extracts/chemistry , Protein Processing, Post-Translational/drug effects , Proteolysis , Radiation Tolerance/drug effects , Transcription Factors/genetics , YAP-Signaling ProteinsABSTRACT
The efficacy of a given drug resides mainly on its ability to specifically target disease mechanisms. Natural products represent the leading source of bioactive molecules with a broad range of activities. It is becoming increasingly clear that natural compounds exert their chemopreventive or antitumoral activities targeting simultaneously diverse cellular pathways. Here we describe the use of antibody array to assess the effects of natural compounds on the expression of multiple proteins and of their posttranslational modifications in cellular systems. This might turn to be a very flexible application for cancer chemoprevention studies.
Subject(s)
Antibodies/immunology , Biological Products/therapeutic use , Drug Evaluation, Preclinical/methods , Neoplasms/prevention & control , Protein Array Analysis/methods , Chemoprevention , Staining and LabelingABSTRACT
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.