title: Prevention of skin carcinogenesis by the β-blocker carvedilol.
abstract: The stress-related catecholamine hormones and the α- and β-adrenergic receptors (α- and β-AR) may affect carcinogenesis. The β-AR GRK/β-arrestin biased agonist carvedilol can induce β-AR-mediated transactivation of the EGFR. The initial purpose of this study was to determine whether carvedilol, through activation of EGFR, can promote cancer. Carvedilol failed to promote anchorage-independent growth of JB6 P(+) cells, a skin cell model used to study tumor promotion. However, at nontoxic concentrations, carvedilol dose dependently inhibited EGF-induced malignant transformation of JB6 P(+) cells, suggesting that carvedilol has chemopreventive activity against skin cancer. Such effect was not observed for the β-AR agonist isoproterenol and the β-AR antagonist atenolol. Gene expression, receptor binding, and functional studies indicate that JB6 P(+) cells only express β2-ARs. Carvedilol, but not atenolol, inhibited EGF-mediated activator protein-1 (AP-1) activation. A topical 7,12-dimethylbenz(α)anthracene (DMBA)-induced skin hyperplasia model in SENCAR mice was utilized to determine the in vivo cancer preventative activity of carvedilol. Both topical and oral carvedilol treatment inhibited DMBA-induced epidermal hyperplasia (P < 0.05) and reduced H-ras mutations; topical treatment being the most potent. However, in models of established cancer, carvedilol had modest to no inhibitory effect on tumor growth of human lung cancer A549 cells in vitro and in vivo. In conclusion, these results suggest that the cardiovascular drug carvedilol may be repurposed for skin cancer chemoprevention, but may not be an effective treatment of established tumors. More broadly, this study suggests that β-ARs may serve as a novel target for cancer prevention.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California.
authors.forename: Andy
authors.initials: A
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California.
authors.forename: Steven
authors.initials: S
authors.lastname: Yeung
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California.
authors.forename: Arvind
authors.initials: A
authors.lastname: Thakkar
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California.
authors.forename: Mandy M
authors.initials: MM
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California.
authors.forename: Rhye-Samuel
authors.initials: RS
authors.lastname: Kanassatega
authors.affiliation: Department of Clinical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, California.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Parsa
authors.affiliation: Department of Clinical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Orlando
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California. yhuang@westernu.edu bandresen@westernu.edu.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Andresen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California. yhuang@westernu.edu bandresen@westernu.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000737:chemistry; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001262:Atenolol / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007545:Isoproterenol / Q000627:therapeutic use; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D011412:Propanolamines / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D016588:Anticarcinogenic Agents; D002227:Carbazoles; D011412:Propanolamines; D018808:Transcription Factor AP-1; D000077261:Carvedilol; D001262:Atenolol; D015127:9,10-Dimethyl-1,2-benzanthracene; D007545:Isoproterenol