ABSTRACT
BACKGROUND: Propranolol (PPL) has been suggested as an option for the treatment of various types of cancer. However, data regarding its effectiveness against oral cancer are scarce. Thus, we aimed to evaluate the antitumor potential of PPL in oral squamous cell carcinoma (OSCC) in vitro. METHODS: OSCC cell lines, SCC-9, SCC-25, and Cal27, were treated with PPL at different times and concentrations. OSCC cells were treated with PPL alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of phosphorylated (p)-Akt, p-S6, p-PTEN, p-P65, and VEGF was verified by immunofluorescence. The migratory activity of OSCC cells was evaluated using a wound-healing assay. RESULTS: PPL reduced OSCC cell viability in a dose- and time-dependent manner. Concentrations above 300 µM, 110 µM, and 100 µM for SCC-9, Cal27, and SCC-25, respectively, significantly eliminated tumor cells. The combination of PPL with CDDP and 5-FU enhanced their antitumor effects. There was a modest difference between the use of the IC30 and IC50 of PPL in the combinatory options. PPL downregulated p-P65 NF-ĸB and VEGF expression in SCC-9 and Cal27 cells but not in SCC-25 cells. PPL inhibited the phosphorylation of Akt and s6 and increased the phosphorylation of PTEN in all OSCC cell lines studied. PPL inhibited OSCC cell migration after 24 h of treatment. CONCLUSION: PPL was effective against oral cancer cells and enhanced standard-of-care. PPL inhibited cell viability and the expression of pAkt, NF-ĸB, and VEGF.
Subject(s)
Mouth Neoplasms , NF-kappa B , Propranolol , Proto-Oncogene Proteins c-akt , Squamous Cell Carcinoma of Head and Neck , Vascular Endothelial Growth Factor A , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Mouth Neoplasms/drug therapy , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , NF-kappa B/antagonists & inhibitors , NF-kappa B/biosynthesis , Propranolol/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/biosynthesis , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/biosynthesisABSTRACT
OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
Subject(s)
Atenolol/therapeutic use , Cytochrome P-450 CYP2C9/genetics , Gene Expression Regulation , Losartan/therapeutic use , Marfan Syndrome/drug therapy , Receptors, Adrenergic, beta-1/genetics , Adolescent , Adrenergic beta-1 Receptor Antagonists/therapeutic use , Adult , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Child , Child, Preschool , Cytochrome P-450 CYP2C9/biosynthesis , DNA/genetics , Female , Follow-Up Studies , Genotype , Humans , Infant , Male , Marfan Syndrome/genetics , Marfan Syndrome/metabolism , Receptors, Adrenergic, beta-1/biosynthesis , Retrospective Studies , Young AdultABSTRACT
Understanding the mechanisms that govern normal mammary gland development is crucial to the comprehension of breast cancer etiology. ß-adrenergic receptors (ß-AR) are targets of endogenous catecholamines such as epinephrine that have gained importance in the context of cancer biology. Differences in ß2-AR expression levels may be responsible for the effects of epinephrine on tumor vs non-tumorigenic breast cell lines, the latter expressing higher levels of ß2-AR. To study regulation of the breast cell phenotype by ß2-AR, we over-expressed ß2-AR in MCF-7 breast cancer cells and knocked-down the receptor in non-tumorigenic MCF-10A breast cells. In MCF-10A cells having knocked-down ß2-AR, epinephrine increased cell proliferation and migration, similar to the response by tumor cells. In contrast, in MCF-7 cells overexpressing the ß2-AR, epinephrine decreased cell proliferation and migration and increased adhesion, mimicking the response of the non-tumorigenic MCF-10A cells, thus underscoring that ß2-AR expression level is a key player in cell behavior. ß-adrenergic stimulation with isoproterenol induced differentiation of breast cells growing in 3-dimension cell culture, and also the branching of murine mammary epithelium in vivo. Branching induced by isoproterenol was abolished in fulvestrant or tamoxifen-treated mice, demonstrating that the effect of ß-adrenergic stimulation on branching is dependent on the estrogen receptor (ER). An ER-independent effect of isoproterenol on lumen architecture was nonetheless found. Isoproterenol significantly increased the expression of ERα, Ephrine-B1 and fibroblast growth factors in the mammary glands of mice, and in MCF-10A cells. In a poorly differentiated murine ductal carcinoma, isoproterenol also decreased tumor growth and induced tumor differentiation. This study highlights that catecholamines, through ß-AR activation, seem to be involved in mammary gland development, inducing mature duct formation. Additionally, this differentiating effect could be resourceful in a breast tumor context.
Subject(s)
Breast Neoplasms/metabolism , Morphogenesis/physiology , Receptors, Adrenergic, beta-2/metabolism , Animals , Breast Neoplasms/drug therapy , Catecholamines/metabolism , Cell Adhesion/drug effects , Cell Adhesion/physiology , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/physiology , Cell Proliferation/drug effects , Cell Proliferation/physiology , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogens/metabolism , Female , Fulvestrant , Humans , Isoproterenol/pharmacology , MCF-7 Cells , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Morphogenesis/drug effects , Receptors, Estrogen/metabolism , Tamoxifen/pharmacologyABSTRACT
The aim of this study was to identify the effect of beta-adrenergic receptor activation on neutrophil migration in experimental peritonitis elucidating the neuroimmune components involved such as nicotinic receptors and the spleen. Mice pre-treated with mecamylamine (nicotinic antagonist) and propranolol (beta-adrenergic antagonist) or splenectomized animals were treated with isoproterenol (beta-adrenergic agonist) prior to intraperitoneal injection of carrageenan. After 4 h, the infiltrating neutrophils and the local cytokine/chemokine levels were evaluated in the peritoneal lavage. The effect of isoproterenol on neutrophil chemotaxis was investigated in a Boyden chamber. Isoproterenol inhibited neutrophil trafficking, reducing the cytokine/chemokine release and neutrophil chemotaxis. Surprisingly, the isoproterenol effect on neutrophil migration was totally reverted by splenectomy and mecamylamine pre-treatment. In contrast, the inhibitory effect of nicotine on neutrophil migration was abrogated only by splenectomy but not by propranolol pre-treatment. Collectively, our data show that beta-adrenergic receptor activation regulates the acute neutrophil recruitment via splenic nicotinic receptor.
Subject(s)
Neutrophil Infiltration/drug effects , Receptors, Adrenergic, beta/metabolism , Receptors, Nicotinic/metabolism , Spleen , Adrenergic beta-Agonists/pharmacology , Animals , Chemotaxis, Leukocyte/drug effects , Cytokines/analysis , Isoproterenol/pharmacology , Mecamylamine/pharmacology , Mice , Nicotinic Antagonists/pharmacology , Peritonitis , Spleen/chemistry , Spleen/metabolism , SplenectomySubject(s)
Autoantibodies/immunology , Chagas Cardiomyopathy/drug therapy , Chagas Cardiomyopathy/immunology , Nitroimidazoles/pharmacology , Receptor, Muscarinic M2/immunology , Receptors, Adrenergic, beta/immunology , Animals , Autoantibodies/blood , Disease Models, Animal , Dogs , Humans , Immunosuppressive Agents/pharmacologyABSTRACT
La patología cardiovascular es la primera causa de muerte en Chile y en el mundo. Desde el punto de vista quirúrgico, anestesiólogos y cirujanos enfrentan más frecuentemente pacientes mayores con patología cardiovascular. La incidencia de isquemia miocárdica en pacientes de alto riesgo, sometidos a cirugía no-cardíaca, es cercana al 40 por ciento durante el perioperatorio. La incidencia de infarto miocárdico y muerte en cirugía no-cardíaca, oscila entre 1 y 5 por ciento. Existe una estrecha relación entre los eventos isquémicos perioperatorios y el aumento de la morbimortalidad cardiovascular. Por este motivo, se han desarrollado medidas terapéuticas orientadas a disminuir la incidencia de isquemia perioperatoria y aminorar el daño asociado a ella. La adecuada identificación de pacientes de riesgo, la optimización del tratamiento médico de patologías asociadas y el uso de fármacos cardioprotectores durante el perioperatorio, han mostrado disminuir la incidencia de complicaciones cardíacas. Dexmedetomidina es un agonista beta2-adrenérgico de uso frecuente en anestesia. La evidencia sugiere que posee propiedades cardioprotectoras que podrían beneficiar a pacientes quirúrgicos de alto riesgo cardiovascular. La cardioprotección conferida por dexmedetomidina estaría mediada por la modulación del sistema nervioso autónomo. La disminución de la frecuencia cardíaca y de la presión arterial observada durante su uso, evitarían el desbalance entre aporte y demanda de oxígeno miocárdico y atenuarían el estrés sobre placas ateromatosas inestables. Hasta este momento se desconoce si dexmedetomidina produce precondicionamiento cardíaco y si activa vías transduccionales asociadas a cardioprotección. Frente a la actual realidad epidemiológica en Chile y el mundo, es importante estudiar y definir, cuales son los fármacos de uso frecuente en anestesia con capacidad cardloprotectora y los mecanismos Involucrados en esta protección. Sería Interesante lograr...
Cardiovascular disease is the leading cause of death In Chile and worldwide. Anesthesiologists and surgeons often face more elderly surgical patients with cardiovascular disease. The incidence of myocardial Ischemia in patents at high risk, undergoing non-cardiac surgery is about 40 percent during the perioperative period. The incidence of myocardial Infarction and death in non-cardiac surgery is between 1 and 5 percent. There is a close relationship between perioperative Ischemic events and increased cardiovascular morbidity and mortality Therefore, therapeutic approaches have been developed to reduce the Incidence of perioperative Ischemia and lessen the damage associated with it. The proper Identification of patients at risk, optimizing the medical treatment of associated diseases and the use of cardioprotective drugs during the perioperative period have shown to decrease the Incidence of cardiac complications. The beta2-adrenergic agonist dexmedetomidine is commonly used in anesthesia. The evidence suggests that possesses cardioprotective properties that could benefit surgical patients at high cardiovascular risk. The cardioprotection conferred by dexmedetomidine would be mediated by modulation of the autonomic nervous system. The decrease in heart rate and blood pressure observed during its use could avoid the Imbalance between supply and myocardial oxygen demand and lessen the stress on unstable athermanous plaques. So far it is unknown whether dexmedetomidine produces cardiac preconditioning by activating cardioprotective-signaling pathways. Faced with the current worldwide epidemiologic situation, It would be Important to study the cardioprotective capacity of drugs frequently used in anesthesia and the mechanisms Involved In that protection. It would be interesting to achieve that definition regarding the perioperative use of dexmedetomidine.