The β‐blocker carvedilol blocks UVB‐induced DNA damage and apoptosis of skin

Abstract

β‐blockers are common pharmacological antagonists of the catecholamine activated β‐adrenergic receptors (β‐ARs). Traditionally prescribed for cardiovascular diseases such as hypertension, this class of drugs has recently been proposed with new uses in cancer treatment and prevention. Our previous studies showed that carvedilol, a nonselective GRK/β‐arrestin biased agonist, prevents skin carcinogenesis in vitro and in vivo. In the present study, we aimed at investigating the effects and mechanism of carvedilol on ultraviolet B (UVB) induced skin DNA damage and apoptosis. To assess the effects of carvedilol in vitro, the tumor promotion sensitive mouse epidermal JB6 P+ cells were treated with H2O2 or UVB to induce cell death and apoptosis. Protective effects of carvedilol was observed through cell counting, SRB cytotoxicity assay and apoptosis assay. Carvedilol effectively prevented H2O2 induced formation of reactive oxygen species in JB6 P+ cells. To explore the mechanism of action, JB6 P+ cells were treated with UVB followed by treatment with carvedilol (to avoid sunscreen effect) in various concentrations and time points. As expected, Western Blot analysis showed that the protein levels of p53 and phospho‐p53 at ser15 were induced by UVB treatment, whereas the effect of UVB on p53 was attenuated by carvedilol. We further examined the effects of topically administered carvedilol on SKH‐1 hairless mice irradiated with a single minimal effective dose (MED) of UVB (200 mJ/cm2). Our results showed that carvedilol protected UVB induced cyclobutene pyrimidine dimer (CPD) formation and apoptosis, 6 and 24 hours after UVB exposure. Consistently, the increased levels of total p53 and phospho‐p53 at Ser15 in mouse skin induced by UVB was decreased after carvedilol treatment. The change in p53 did not occur at the mRNA level, given RT‐PCR analysis failed to detect any change in the Tp53 gene. From these results, we conclude that carvedilol exhibits a protective effect against UVB induced DNA damage and apoptosis, partly related to its effect on UVB‐induced p53. These results further support the notion that the β‐blocker carvedilol may be re‐purposed for skin cancer prevention.