Prevention of skin carcinogenesis by the non-β-blocking R-carvedilol enantiomer.

Skin cancer is the most common malignancy worldwide and is rapidly rising in incidence, representing a significant public health challenge. The β-blocker carvedilol has shown promising effects in preventing skin cancer. However, as a potent β-blocker, repurposing carvedilol to an anticancer agent is limited by cardiovascular effects. Carvedilol is a racemic mixture consisting of equimolar S- and R-carvedilol, whereas the R-carvedilol enantiomer does not possess β-blocking activity. Since previous studies suggest that carvedilol's cancer-preventive activity is independent of β-blockade, we examined the skin cancer preventive activity of R-carvedilol compared with S-carvedilol and the racemic carvedilol. R- and S-carvedilol were equally effective in preventing epidermal growth factor (EGF)-induced neoplastic transformation of the mouse epidermal JB6 P+ cells and displayed similar attenuation of EGF-induced ELK-1 activity. R-carvedilol appears slightly better than S-carvedilol against ultraviolet (UV)-induced intracellular oxidative stress and release of Prostaglandin E2 from the JB6 P+ cells. In an acute UV induced skin damage and inflammation mouse model using a single irradiation of 300 mJ/cm2 UV, topical treatment with R-carvedilol dose-dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, IL-6 and IL-1β mRNA levels similar to carvedilol. In a chronic UV (50-150 mJ/cm2) induced skin carcinogenesis model in mice with pretreatment of test agents, topical treatment with R-carvedilol, but not racemic carvedilol, significantly delayed and reduced skin squamous cell carcinoma development. Therefore, as an enantiomer present in an FDA-approved agent, R-carvedilol may be a better option for developing a safer and more effective preventive agent for skin carcinogenesis.