Abstract
In previous studies, the β-blocker carvedilol inhibited EGF-induced epidermal cell transformation and chemical carcinogen-induced mouse skin hyperplasia. As exposure to ultraviolet (UV) radiation leads to skin cancer, the present study examined whether carvedilol can prevent UV-induced carcinogenesis. Carvedilol absorbs UV like a sunscreen; thus, to separate pharmacological from sunscreen effects, 4-hydroxycarbazole (4-OHC), which absorbs UV to the same degree as carvedilol, served as control. JB6 P+ cells, an established epidermal model for studying tumor promotion, were used for evaluating the effect of carvedilol on UV-induced neoplastic transformation. Both carvedilol and 4-OHC (1 μmol/L) blocked transformation induced by chronic UV (15 mJ/cm2) exposure for 8 weeks. However, EGF-mediated transformation was inhibited by only carvedilol but not by 4-OHC. Carvedilol (1 and 5 μmol/L), but not 4-OHC, attenuated UV-induced AP-1 and NF-κB luciferase reporter activity, suggesting a potential anti-inflammatory activity. In a single-dose UV (200 mJ/cm2)-induced skin inflammation mouse model, carvedilol (10 μmol/L), applied topically after UV exposure, reduced skin hyperplasia and the levels of cyclobutane pyrimidine dimers, IL1β, IL6, and COX-2 in skin. In SKH-1 mice exposed to gradually increasing levels of UV (50-150 mJ/cm2) three times a week for 25 weeks, topical administration of carvedilol (10 μmol/L) after UV exposure increased tumor latency compared with control (week 18 vs. 15), decreased incidence and multiplicity of squamous cell carcinomas, while 4-OHC had no effect. These data suggest that carvedilol has a novel chemopreventive activity and topical carvedilol following UV exposure may be repurposed for preventing skin inflammation and cancer. Cancer Prev Res; 10(10); 598-606. ©2017 AACR.
Highlights
Introduction bAdrenergic receptor (b-AR) antagonists, commonly called b-blockers, are usually used for cardiovascular disorders and act via inhibiting catecholamines, i.e., epinephrine and norepinephrine, from triggering the body's "fight or flight" response to stress [1]
Recent evidence suggests that catecholamines, by activating bAdrenergic receptor (b-AR), play a role in carcinogenesis including skin carcinogenesis, possibly through inducing DNA damage [2], promoting transformation [3, 4], and inhibiting cutaneous immunity [5]. b-ARs are expressed in various cell types of human skin
Carvedilol and 4-OHC were reconstituted in dimethyl sulfoxide (DMSO) used in vitro or in acetone used in vivo, whereas epidermal growth factor (EGF) was prepared in PBS
Summary
Compounds Carvedilol was purchased from Tocris Bioscience. 4-Hydroxycarbazole (4-OHC) and 1,2-dimethoxybenzene was purchased from Sigma-Aldrich and epidermal growth factor (EGF) from Peprotech. Mice were topically treated with 200 mL acetone (vehicle), 10 mmol/L carvedilol or 4-OHC dissolved in 200 mL acetone three times per week for 2 weeks before UV exposure. The concentration-response effects of carvedilol and 4-OHC on EGF-mediated transformation of JB6 Pþ cells were examined (Fig. 1B). Carvedilol inhibited EGF-induced JB6 Pþ cell transformation in a dose-dependent manner [29], but 4-OHC had no effect. As 4-OHC absorbs UV irradiation, it is expected that 4-OHC will have some degree of UV protection, while carvedilol is hypothesized to provide greater preventive activity against UVinduced effects due to its pharmacological activity This hypothesis was first tested in the JB6 Pþ cell transformation assay using UV as the tumor promoter because low and re-occurring dosages. Specific statistical tests are detailed in the figure legends or text; for data dealing with tumor number, data are reported as median Æ median absolute deviation (MAD), and nonparametric analysis was used for statistical quantification
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