Carvedilol inhibits EGF-mediated JB6 P+ colony formation through a mechanism independent of adrenoceptors
| Autor: | Andy Chang, Kristan H. Cleveland, Kevin M. Huang, Si Chen, Bradley T. Andresen, Ying Huang, Lei Guo, Sherry Liang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Skin Neoplasms MTS assay Cancer Treatment Pharmacology Ligands Toxicology Pathology and Laboratory Medicine Cell Transformation Mice chemistry.chemical_compound 0302 clinical medicine Epidermal growth factor Medicine and Health Sciences Enzyme assays Colorimetric assays RNA Small Interfering Receptor Bioassays and physiological analysis Carvedilol Skin Cytotoxicity Assay Multidisciplinary integumentary system Animal Models Receptors Adrenergic Cell Transformation Neoplastic Experimental Organism Systems Oncology Optical Equipment 030220 oncology & carcinogenesis Medicine Engineering and Technology medicine.symptom Cancer Prevention Signal Transduction Research Article medicine.drug Cell Physiology Ultraviolet Rays Science Adrenergic beta-Antagonists Equipment Mouse Models Research and Analysis Methods Chemoprevention Cell Line Inhibitory Concentration 50 03 medical and health sciences Model Organisms In vivo Receptors Adrenergic beta medicine Animals Labetalol Alprenolol Cell Proliferation Epidermal Growth Factor Toxicity Cell growth Biology and Life Sciences Prisms Cell Biology Mice Inbred C57BL 030104 developmental biology chemistry Mechanism of action Biochemical analysis Animal Studies Tumor promotion |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 5, p e0217038 (2019) |
| ISSN: | 1932-6203 |
| Popis: | Carvedilol is reported to prevent cancers in humans and animal models. However, a molecular mechanism has yet to be established, and the extent to which other β-blockers are chemopreventive remains relatively unknown. A comparative pharmacological approach was utilized with the expectation that a mechanism of action could be devised. JB6 Cl 41-5a (JB6 P+) murine epidermal cells were used to elucidate the chemopreventative properties of β-blockers, as JB6 P+ cells recapitulate in vivo tumor promotion and chemoprevention. The initial hypothesis was that β-blockers that are GRK/β-arrestin biased agonists, like carvedilol, are chemopreventive. Sixteen β-blockers of different classes, isoproterenol, and HEAT HCl were individually co-administered with epidermal growth factor (EGF) to JB6 P+ cells to examine the chemopreventative properties of each ligand. Cytotoxicity was examined to ensure that the anti-transformation effects of each ligand were not due to cellular growth inhibition. Many of the examined β-blockers suppressed EGF-induced JB6 P+ cell transformation in a non-cytotoxic and concentration-dependent manner. However, the IC50 values are high for the most potent inhibitors (243, 326, and 431 nM for carvedilol, labetalol, and alprenolol, respectively) and there is no correlation between pharmacological properties and inhibition of transformation. Therefore, the role of α1- and β2-adrenergic receptors (AR) was examined by standard competition assays and shRNA targeting β2-ARs, the only β-AR expressed in JB6 P+ cells. The results reveal that pharmacological inhibition of α1- and β2-ARs and genetic knockdown of β2-ARs did not abrogate carvedilol-mediated inhibition of EGF-induced JB6 P+ cell transformation. Furthermore, topical administration of carvedilol protected mice from UV-induced skin damage, while genetic ablation of β2-ARs increased carvedilol-mediated effects. Therefore, the prevailing hypothesis that the chemopreventive property of carvedilol is mediated through β-ARs is not supported by this data. |
| Databáze: | OpenAIRE |
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