Topically Applied Carvedilol Attenuates Solar Ultraviolet Radiation Induced Skin Carcinogenesis

Abstract

In previous studies, the β-blocker carvedilol inhibited EGF-induced epidermal cell transformation and chemical carcinogen-induced mouse skin hyperplasia. As exposure to ultraviolet (UV) radiation leads to skin cancer, the present study examined whether carvedilol can prevent UV-induced carcinogenesis. Carvedilol absorbs UV like a sunscreen; thus, to separate pharmacological from sunscreen effects, 4-hydroxycarbazole (4-OHC), which absorbs UV to the same degree as carvedilol, served as control. JB6 P cells, an established epidermal model for studying tumor promotion, were used for evaluating the effect of carvedilol on UV-induced neoplastic transformation. Both carvedilol and 4-OHC (1 μmol/L) blocked transformation induced by chronic UV (15 mJ/cm) exposure for 8 weeks. However, EGF-mediated transformation was inhibited by only carvedilol but not by 4-OHC. Carvedilol (1 and 5 μmol/L), but not 4-OHC, attenuated UV-induced AP-1 and NF-κB luciferase reporter activity, suggesting a potential anti-inflammatory activity. In a single-dose UV (200 mJ/cm)-induced skin inflammation mouse model, carvedilol (10 μmol/L), applied topically after UV exposure, reduced skin hyperplasia and the levels of cyclobutane pyrimidine dimers, IL1β, IL6, and COX-2 in skin. In SKH-1 mice exposed to gradually increasing levels of UV (50-150 mJ/cm) three times a week for 25 weeks, topical administration of carvedilol (10 μmol/L) after UV exposure increased tumor latency compared with control (week 18 vs. 15), decreased incidence and multiplicity of squamous cell carcinomas, while 4-OHC had no effect. These data suggest that carvedilol has a novel chemopreventive activity and topical carvedilol following UV exposure may be repurposed for preventing skin inflammation and cancer. .

Phosphoproteome profiling provides insight into the mechanism of action for carvedilol‐mediated cancer prevention

“…As carvedilol, a β‐arrestin‐biased β‐blocker, stimulates phosphorylation of ERK, and due to known effects of ERK in carcinogenesis, our initial hypothesis was that carvedilol may cause cancer. However, the data we obtained collectively thus far support a revised hypothesis that carvedilol is a cancer preventive agent . The present study was aimed at identifying the potential mechanism for carvedilol's preventive effect on JB6 P+ cell transformation.…”

“…Although current data using A375 xenograft (melanoma with B‐RAF activating mutation) (Figure ) support our hypothesis, the extent and cancer relevance of the cytosolic retention effect on ERK remain to be investigated for carvedilol as well as other biased β‐blockers. In addition, carvedilol and other β‐blockers have been reported to modulate other cancer‐associated pathways, such as COX‐2, AKT, PKC, and PDGF signaling. Many of these pathways can be modulated by EGF and downstream ERK signaling.…”

“…However, the data we obtained collectively thus far support a revised hypothesis that carvedilol is a cancer preventive agent. 23,24 The present study was aimed at identifying the potential mechanism for carvedilol's preventive effect on JB6 P+ cell transformation. To our knowledge, this is the first study addressing the new role for β-arrestin biased β-blockers in cancer prevention.…”

“…23 Carvedilol's cancer preventative attributes were further confirmed in vitro and in vivo. 23,24 Consistently, a recent population-based cohort study reported that long-term use of carvedilol is associated with reduced risk of many types of cancer. 25 To identify the mechanisms underlying the cancer preventive activity of carvedilol on JB6 P+ cells, the present study determined whether carvedilol is able to activate ERK in JB6 P+ cells and further addressed the question why as an ERK activator carvedilol does not promote but oppositely prevent EGF-induced transformation.…”

“…However, the initial data proved the hypothesis incorrect and further experimental data suggested the opposite: carvedilol, when mixed with the tumor promoter EGF, prevented transformation of JB6 P+ cells . Carvedilol's cancer preventative attributes were further confirmed in vitro and in vivo . Consistently, a recent population‐based cohort study reported that long‐term use of carvedilol is associated with reduced risk of many types of cancer …”