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1.
Cell Death Dis ; 14(9): 613, 2023 09 19.
Article in English | MEDLINE | ID: mdl-37723219

ABSTRACT

The ß2-Adrenergic receptor (ß2-ARs) is a cell membrane-spanning G protein-coupled receptors (GPCRs) physiologically involved in stress-related response. In many cancers, the ß2-ARs signaling drives the tumor development and transformation, also promoting the resistance to the treatments. In HNSCC cell lines, the ß2-AR selective inhibition synergistically amplifies the cytotoxic effect of the MEK 1/2 by affecting the p38/NF-kB oncogenic pathway and contemporary reducing the NRF-2 mediated antioxidant cell response. In this study, we aimed to validate the anti-tumor effect of ß2-AR blockade and the synergism with MEK/ERK and EGFR pathway inhibition in a pre-clinical orthotopic mouse model of HNSCC. Interestingly, we found a strong ß2-ARs expression in the tumors that were significantly reduced after prolonged treatment with ß2-Ars inhibitor (ICI) and EGFR mAb Cetuximab (CTX) in combination. The ß2-ARs down-regulation correlated in mice with a significant tumor growth delay, together with the MAPK signaling switch-off caused by the blockade of the MEK/ERK phosphorylation. We also demonstrated that the administration of ICI and CTX in combination unbalanced the cell ROS homeostasis by blocking the NRF-2 nuclear translocation with the relative down-regulation of the antioxidant enzyme expression. Our findings highlighted for the first time, in a pre-clinical in vivo model, the efficacy of the ß2-ARs inhibition in the treatment of the HNSCC, remarkably in combination with CTX, which is the standard of care for unresectable HNSCC.


Subject(s)
Antioxidants , Head and Neck Neoplasms , Animals , Mice , Squamous Cell Carcinoma of Head and Neck , Oxidative Stress , Antibodies , Cetuximab/pharmacology , Cetuximab/therapeutic use , ErbB Receptors , Mitogen-Activated Protein Kinase Kinases
2.
Nutrients ; 15(3)2023 Jan 21.
Article in English | MEDLINE | ID: mdl-36771270

ABSTRACT

Trimethylamine N-oxide (TMAO) is a microbial metabolite derived from nutrients, such as choline, L-carnitine, ergothioneine and betaine. Recently, it has come under the spotlight for its close interactions with gut microbiota and implications for gastrointestinal cancers, cardiovascular disease, and systemic inflammation. The culprits in the origin of these pathologies may be food sources, in particular, high fat meat, offal, egg yolk, whole dairy products, and fatty fish, but intercalated between these food sources and the production of pro-inflammatory TMAO, the composition of gut microbiota plays an important role in modulating this process. The aim of this review is to explain how the gut microbiota interacts with the conversion of specific compounds into TMA and its oxidation to TMAO. We will first cover the correlation between TMAO and various pathologies such as dysbiosis, then focus on cardiovascular disease, with a particular emphasis on pro-atherogenic factors, and then on systemic inflammation and gastrointestinal cancers. Finally, we will discuss primary prevention and therapies that are or may become possible. Possible treatments include modulation of the gut microbiota species with diets, physical activity and supplements, and administration of drugs, such as metformin and aspirin.


Subject(s)
Cardiovascular Diseases , Microbiota , Neoplasms , Animals , Choline/metabolism , Methylamines/metabolism , Inflammation , Neoplasms/drug therapy , Neoplasms/prevention & control
3.
J Cardiovasc Dev Dis ; 9(12)2022 Nov 28.
Article in English | MEDLINE | ID: mdl-36547420

ABSTRACT

Anthracyclines are essential adjuvant therapies for a variety of cancers, particularly breast, gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Spirulina, Reishi (Ganoderma lucidum) and Moringa are three nutraceuticals with anti-inflammatory effects that are currently used in cancer patients as complementary and alternative medicines to improve quality of life and fatigue. We hypothesize that the nutraceutical combination of Spirulina, Reishi and Moringa (Singo) could reduce inflammation and cardiotoxicity induced by anthracyclines. Female C57Bl/6 mice were untreated (Sham, n = 6) or treated for 7 days with short-term doxorubicin (DOXO, n = 6) or Singo (Singo, n = 6), or pre-treated with Singo for 3 days and associated with DOXO for remaining 7 days (DOXO−Singo, n = 6). The ejection fraction and radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100, Fujifilm, Tokyo, Japan). The myocardial expressions of NLRP3, DAMPs (galectin-3 and calgranulin S100) and 13 cytokines were quantified through selective mouse ELISA methods. Myocardial fibrosis, necrosis and hypertrophy were analyzed through immunohistochemistry (IHC). Human cardiomyocytes were exposed to DOXO (200 nM) alone or in combination with Singo (at 10, 25 and 50 µg/mL) for 24 and 48 h. Cell viability and inflammation studies were also performed. In preclinical models, Singo significantly improved ejection fraction and fractional shortening. Reduced expressions of myocardial NLRP3 and NF-kB levels in cardiac tissues were seen in DOXO−Singo mice vs. DOXO (p < 0.05). The myocardial levels of calgranulin S100 and galectin-3 were strongly reduced in DOXO−Singo mice vs. DOXO (p < 0.05). Immunohistochemistry analysis indicates that Singo reduces fibrosis and hypertrophy in the myocardial tissues of mice during exposure to DOXO. In conclusion, in the preclinical model of DOXO-induced cardiotoxicity, Singo is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis.

4.
Infect Agent Cancer ; 10: 22, 2015.
Article in English | MEDLINE | ID: mdl-26225138

ABSTRACT

BACKGROUND: Human pancreatic cancer is currently one of the deadliest cancers with high mortality rate. It has been previously shown that (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin found in green tea, has showed suppressive effects on human pancreatic cancer cells. Bleomycin, (BLM), an anti-cancer chemotherapeutic drug that induces DNA damage, has antitumor effects by induction of apoptosis in several cancer cell lines and also in pancreatic cancer cells. The present study investigated for the first time, the inhibitory effect of EGCG and BLM on pancreatic cancer cell growth. METHODS: Using the pancreatic cancer cell lines MIA PaCa-2 cells the efficacy and synergism of EGCG and BLM were evaluated by in vitro tests. Inhibition of cell proliferation was determined by MTT assay. Mitochondrial depolarization was performed with JC-1 probe. Viability and apoptosis were determined by Flow Cytometry with annexin V, propidium iodide staining and DNA fragmentation assay. RESULTS: Cell proliferation assay revealed significant additive inhibitory effects with combination of EGCG and BLM at 72 h in a dose dependent manner. The combination of EGCG and BLM induced cell cycle S-phase arrest and mitochondrial depolarization. Viability, apoptosis and DNA fragmentation assay indicated that the combination of EGCG and bleomycin potentiated apoptosis. CONCLUSIONS: Our results indicate that EGCG and BLM have additive anti-proliferative effects in vitro by induction of apoptosis of MIA PaCa-2 cells. This combination could represent a new strategy with potential advantages for treatment of pancreatic cancer. To date, this is the first report published of the inhibitory effect of EGCG and BLM on human pancreatic cancer MIA Paca-2 cell growth.

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