Abstract 2617: Protective effect of the β-blocker carvedilol on UVB-induced skin damage

Abstract

Abstract The response to ultraviolet (UV) radiation is the primary etiologic factor leading to carcinogenesis of the skin. The effects of UV radiation on the skin is generally transient, but the long term consequences can be carcinogenic. Despite growing public awareness and the use of sunscreen to prevent skin cancer, the incidence continues to rise, and therefore there is a need to develop innovative chemoprevention strategies. Previously, we showed that the receptor subtype nonselective β-adrenergic receptor antagonist (i.e., β-blocker) carvedilol prevented EGF and UVB-mediated neoplastic transformation of the mouse epidermal cell line JB6 P+, indicating its chemopreventive potential against skin cancer. To demonstrate the in vivo effects of carvedilol, in the present study, hairless SKH-1 mice were irradiated for two weeks with 200 mJ/cm2 of UVB and drugs were topically applied immediately after the radiation. Since carvedilol is able to absorb UV, its analogue 4-hydroxycarbazole, which has the same UVB absorption profiling as carvedilol but does not function as a β-blocker, was included as a sunscreen control. Significant skin thickening measured by bi-fold skin thickness on the dorsal skin was observable within a week and over the course of the two-week period. Treatment with carvedilol, but not the analogue, reduced UVB-induced skin hyperplasia, reddening and inflammation. Furthermore, carvedilol, but not the analogue, reduced H2O2 and UVB- induced cytotoxicity and reactive oxygen species production in JB6 P+ cells. To elucidate the molecular mechanism(s) for carvedilol's chemopreventive activity, the signaling profile for JB6 P+ cells treated with EGF and/or carvedilol for 15 min was examined using a Phospho Explorer Antibody Microarray containing 1318 site and phosphor-specific antibodies from over 30 signaling pathways. The antibody array data suggested that the phosphorylation of the intracellular signaling pathways involved in skin carcinogenesis, AP-1 and NF-kB, were increased by EGF but attenuated by carvedilol. These results were validated using luciferase reporter assays. The array data also suggested that carvedilol was able to induce the expression of tumor suppressors p53 and PTEN. In addition, the checkpoint kinases CHK1 and CHK2 and other cell-cycle regulators such as cyclins were also upregulated by carvedilol, suggesting a role in carvedilol's protective effect. Since highly abundant mutations are observable in sun-exposed skin, our current work is to examine the effects of carvedilol on the production of cyclo-pyrimidine dimers (CPDs) induced by UVB. In conclusion, our study has demonstrated novel mechanisms underlying carvedilol's chemopreventive activity against skin cancer. Since carvedilol and other β-blockers are FDA approved drugs and relatively safe, they may offer a new approach of prevention for UVB-induced skin cancer. Citation Format: Kevin M. Huang, Kristan H. Cleveland, Steven Yeung, Bradley T. Andresen, Ying Huang. Protective effect of the β-blocker carvedilol on UVB-induced skin damage. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2617.