The β-Blocker Carvedilol Prevented Ultraviolet-Mediated Damage of Murine Epidermal Cells and 3D Human Reconstructed Skin

Mengbing Chen,Ying Huang,Sherry Liang,Bradley T Andresen,Ayaz Shahid

doi:10.3390/ijms21030798

Abstract

The β-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but the mechanism is unknown. Since carvedilol possesses antioxidant activity, this study investigated whether carvedilol prevents oxidative photodamage of skin, a precursor event in skin carcinogenesis. The effects of carvedilol, metoprolol (a β-blocker without antioxidant property), and 4-hydroxycarbazole (4-OHC, a carvedilol synthesis intermediate and a free radical scavenger) were compared on UV- or H2O2-induced cell death and reactive oxygen species (ROS) production in murine epidermal JB6 P+ cells. Although carvedilol attenuated cell death, metoprolol and 4-OHC failed to show protective effects. As expected, increased cellular ROS induced by H2O2 or UV was abolished by carvedilol and 4-OHC, but not by metoprolol. Consistently, carvedilol attenuated the formation of UV-induced cyclobutane pyrimidine dimers (CPDs) and release of prostaglandin E2 in JB6 P+ cells. Carvedilol’s activity was further confirmed in full thickness 3D human reconstituted skin, where carvedilol attenuated UV-mediated epidermal thickening, the number of Ki-67 and p53 positive cells as well as CPD formation. Based on pathway-specific Polymerase Chain Reaction (PCR) Array analysis, carvedilol treatment in many cases normalized UV-induced expression changes in DNA repair genes. Thus, carvedilol’s photoprotective activity is not attributed to β-blockade or direct ROS-scavenging capacity, but likely via DNA repair regulation.

Highlights

The β-adrenergic receptor (β-AR) antagonists, commonly called β-blockers, are traditionally used for cardiovascular disorders [1]
Carvedilol at 0.1 to 5.0 μM dose-dependently prevented UV-induced cell death with 5.0 μM displaying no significant difference than the controls (Figure 1A)
The UV-associated viability and reactive oxygen species (ROS) studies confirm previous studies that carvedilol may not act through the β-Ars in skin cells [10], but cannot exclude the possibility that ROS suppression may be its protective mechanism against UV-induced epidermal cell death

Summary

Introduction

The β-adrenergic receptor (β-AR) antagonists, commonly called β-blockers, are traditionally used for cardiovascular disorders [1]. These agents act by binding to the β-ARs and thereby inhibiting catecholamines from triggering the body’s “fight or flight” response to stress [2]. Recent data demonstrate that carvedilol prevents malignant transformation and carcinogenesis induced by epidermal growth factor (EGF), chemical carcinogens, and UV [6,7,8,9]. Since all β-blockers inhibit β-ARs, the stand-out cancer preventive activity of carvedilol suggests that the mechanism might be associated with a unique property of carvedilol and that the β-ARs may not be the direct target for carvedilol’s cancer preventive activity [10]

Methods

Results

Discussion

Conclusion