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 epidermal growth factor receptor (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 non-toxic 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.

Phosphoproteome profiling provides insight into the mechanism of action for carvedilol‐mediated cancer prevention

“…Previous studies have shown that the biased β‐blockers induced ERK1/2 phosphorylation in HEK‐293 cells transfected with β2‐AR . We therefore examined if carvedilol has the same property in JB6 P+ cells which was confirmed to express endogenous β2‐AR . We also evaluated EGF in term of its ability to induce ERK1/2 phosphorylation in JB6 P+ cells for comparison.…”

“…AP‐1 is a heterodimeric complex containing c‐Jun and c‐Fos and induced AP‐1 activity is required for EGF‐induced JB6 transformation . As carvedilol, but not the unbiased β‐blocker atenolol, inhibited EGF‐mediated activation of AP‐1, we next used a dual‐luciferase reporter assay to examine the effect of biased β‐blocker alprenolol and unbiased β‐blocker metoprolol on EGF‐induced AP‐1 promoter activity. At 1 and 10 μM, alprenolol alone had no effect on AP‐1 activity, but strongly attenuated EGF‐induced activation of AP‐1 to the same level of the negative control (Figure A), However, metoprolol had no effect on EGF‐mediated AP‐1 activity.…”

“…As carvedilol stimulates β‐arrestin‐mediated phosphorylation of ERK and due to known role of ERK in carcinogenesis, our initial hypothesis was that carvedilol may promote cancer. We therefore, examined the effects of carvedilol alone on the neoplastic transformation of JB6 Cl 41‐5a (JB6 P+) cells, which are non‐cancerous cells that are known to be transformable and form colonies in soft agar after exposure to several tumor promoters, such as EGF . However, the initial data proved the hypothesis incorrect and further experimental data suggested the opposite: carvedilol, when mixed with the tumor promoter EGF, prevented transformation of JB6 P+ cells .…”

β-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do β₃-Adrenoceptors Play a Role?

“…In keeping with this suggestion, refractory cancer may be successfully treated with β-adrenoceptor blockers combined with chemotherapy [81], but the mechanisms of action beyond specific β-adrenoceptor subtype blockade are not evident. For example, Chang et al [82] showed that EGF-induced AP-1 transactivation: (i) remained unaffected by atenolol (a β-blocker with a very low affinity for β 3 -adrenoceptors) [54,63] at any dose tested (which is required for tumor promotion) and (2) was prevented by carvedilol (a nonselective β-blocker with a high affinity for β 3 -adrenoceptors; Table 1). The simplest interpretation of these findings may be that, apart from the β 1 / β 2 -mediated actions, some affinity for β 3 -adrenoceptors may be a conditio sine qua non for their antiproliferative actions.…”

NO-dependent attenuation of TPA-induced immunoinflammatory skin changes in Balb/c mice by pindolol, heptaminol or ATRA, but not by verapamil

“…Furthermore, a recent chemical mouse skin carcinogenesis study on immunocompetent SENCAR mice demonstrated that oral or topical carvedilol, but not atenolol, exerted antitumor-promoting activity by suppressing the skin inflammation and epidermal hyperplasia [8]. Also, in an animal study modeling the pulmonary metastatic effects of surgery stress using immunocompetent F344 rats and MADB106 breast cancer cell line, non-specific β-blocker nadolol was shown to exert its antimetastitic effects in lungs by attenuating the stress-induced reduction in pulmonary-marginating natural killer cell (NK cell) numbers and individual NK cell activity [9].…”