Abstract 1915: Effects of carvedilol, a β-adrenergic receptor antagonist, on UVB-induced skin cancer development and its possible mechanism of action

Recently, we proposed that carvedilol, a β-adrenergic receptor antagonist (i.e., β-blocker), can act as a chemopreventive agent against skin cancer (Chang et al., Cancer Prev. Res, 2014). Since approximately 90 percent of diagnosed non-melanoma skin cancers are associated with exposure to ultraviolet (UV) radiation from the sun, the primary form being UVB irradition, we hypothesized that carvedilol will prevent UVB-induced skin carcinogenesis. The transformable JB6 P+ cell line, an established model for studying skin cancer promotion, was used for evaluating the impact of carvedilol on UVB-induced oxidative damage. Exposures of JB6 P+ cells to 50 - 400 mJ/cm2 UVB resulted in a dose-dependent decrease in cell viability. 25 mJ/cm2 UVB induced ∼20% of cell death, and thus was chosen to study the effect of carvedilol. 0.1 to 1.0 μM carvedilol prevented UVB-induced growth inhibition and apoptosis; however, 3 to 5 μM carvedilol, although nontoxic alone, enhanced UVB-induced cell death. Contrarily, all concentrations of carvedilol tested blocked H2O2-dependent cytotoxicity of JB6 P+ cells. Thus, although both UVB and H2O2 are classic inducers of oxidative stress resulting in DNA damage and tumor promotion, carvedilol may modulate UVB and H2O2-mediated effects via different mechanisms. Cell signaling studies revealed that carvedilol inhibited EGF-induced phosphorylation of AKT at S473 and GSK3β at S9 as well as AP-1 transactivation, which are all well-known principal mediators of skin carcinogenesis. A pitfall with experiments involving UV exposure is the potential UV absorption properties of test compounds. Examination of the structure of carvedilol indicates that it will absorb UV due to the presence of a carbazole moiety and benzene rings. If not controlled in the experiments, the observed effects will be a mixture of pharmacological properties and a UV absorption effect. To identify a solution for this problem, 4-hydroxycarbazole, which mimicks the carbazole moiety of carvedilol, was found to have the same UVB absorption properties as carvedilol but does not function as a β-adrenergic receptor antagonist nor inhibit EGF-mediated colony formation of JB6 P+ cells. 4-hydroxycarbazole is currently being used to repeat the UVB experiments mentioned above to act as a sunscreen/absorption control. Additionally, 4-hydroxycarbazole should be used as a control for carvedilol for other on-going studies for prevention of UVB-induced skin cancer. Since 4-hydroxycarbazole only has the UV absorption (i.e., sunscreen) effect, we anticipate that it will have some protective effect, but that carvedilol provides greater preventive activity against UVB-induced skin carcinogenesis. Since carvedilol and other β-blockers are already FDA-approved drugs, these results may be readily translated into clinical trials as a new approach for skin cancer chemoprevention. Citation Format: Kevin M. Huang, Andy Chang, Kristan H. Cleveland, Bradley T. Andresen, Ying Huang. Effects of carvedilol, a β-adrenergic receptor antagonist, on UVB-induced skin cancer development and its possible mechanism of action. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1915. doi:10.1158/1538-7445.AM2015-1915