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

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.

Topical Delivery of Carvedilol Loaded Nano-Transfersomes for Skin Cancer Chemoprevention

“…Previous studies have indicated that the β-blocker carvedilol, commonly used to manage cardiovascular disorders such as hypertension and heart failure, showed promising activity in preventing chemical carcinogen and UV-induced skin carcinogenesis in vitro and in vivo [3,4]. The anticancer mechanisms for carvedilol involve multifunctional action including attenuating UV-induced oxidative stress, DNA damage, inflammation, and oncogenic signaling pathways [4,5]. Further supporting a role of carvedilol in cancer prevention, a population-based cohort study of 6771 individuals demonstrated that long-term use of carvedilol was associated with a reduced risk of several types of cancer [6].…”

Prevention of Skin Carcinogenesis by the Non-β-blocking R-carvedilol Enantiomer

“…Identifying the unknown targets for carvedilol could have significant implications for understanding carcinogenesis and chemoprevention of cancer as well as the development of new cancer-preventive strategies. Thus far, studies examining the mechanism of action of carvedilol eliminated β-blockade (15) and likely eliminated scavaging ROS (28) as chemopreventive mechanisms. In this study, the R-carvedilol concentration-response curves generated from the soft agar colony formation assay suggest that there are either multiple binding sites displaying negative cooperation or multiple targets involved with varying affinities.…”

Keratinocyte Carcinoma and Photoprevention: The Protective Actions of Repurposed Pharmaceuticals, Phytochemicals and Vitamins

“…In vitro studies reported that following carvedilol treatment, irradiated cells exhibited reductions in NF-κB and AP-1 activity, PGE 2 release and colony formation [89,90], whereas topical application in reconstituted human skin reduced inflammation markers such as COX-2 and TNF-α expression, as well as hyperplasia and apoptosis [91]. Furthermore, carvedilol treatment decreased inflammatory cytokines and CPDs in hairless mice when photocarcinogenesis is stimulated experimentally.…”