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 beta-blocker, carvedilol, has shown promising effects in preventing skin cancer. However, as a potent b-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 beta-blocking activity. Because previous studies suggest that carvedilol's cancer preventive activity is independent of beta-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 EGF-induced neoplastic transformation of the mouse epidermal JB6 Cl 41-5a (JB6 P+) cells and displayed similar attenuation of EGF-induced ELK-1 activity. R-carvedilol appeared slightly better than S-carvedilol against 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/cm(2) UV, topical treatment with R-carvedilol dose dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, and IL6 and IL1 beta mRNA levels similar to carvedilol. In a chronic UV (50-150 mJ/cm(2)) 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. Prevention Relevance: In this study, we demonstrated the skin cancer preventive activity of R-carvedilol, the non-beta-blocking enantiomer present in the racemic beta-blocker, carvedilol. As R-carvedilol does not have beta-blocking activity, such a preventive treatment would not lead to common cardiovascular side effects of beta-blockers.

Automated summary

This study demonstrates that R-carvedilol, a non-beta-blocking enantiomer of the racemic beta-blocker carvedilol, has promising preventive effects against skin cancer. It effectively prevents EGF-induced neoplastic transformation and UV-induced oxidative stress in skin cells, as well as delays and reduces the development of skin squamous cell carcinoma in mouse models. This suggests that R-carvedilol may be a safer and more effective option for skin cancer prevention without the common cardiovascular side effects associated with beta-blockers.