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

Abstract

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 Scarvedilol 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 E 2 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 Rcarvedilol 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/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.

β‐Adrenergic signaling in skin cancer

“…Another study also supported the potential of carvedilol for use in skin cancer prevention 24 . Of note, however, the study also found that carvedilol's non–β‐blocking enantiomer, R‐carvedilol, may be better for treating patients because it has fewer adverse effects than carvedilol.…”

“…Thus, R-carvedilol may be a safer and more effective alternative to carvedilol for preventing skin cancer. 24 Other researchers are exploring whether the mode of delivery of βblockers could offer an alternative oral carvedilol with fewer adverse effects for treating skin cancer. One study demonstrated that various doses of carvedilol packaged into transferosomes made of phospholipids and surfactants and delivered topically suppressed UVinduced DNA damage and inflammatory gene expression and promoted apoptosis.…”

Topical carvedilol delivery prevents UV-induced skin cancer with negligible systemic absorption

“…Female SKH-1 hairless mice, seven-eight week of age, were randomly divided into five groups (n = 5): (1) no UV negative control, (2) UV + acetone, (3) UV + 10 uM carvedilol in acetone (10 µM or 4 μg/mL, 0.8 μg per treatment), (4) UV + empty transfersomes gel formulation, and (5) UV + T-CAR gel formulation. The UV lamps used in these studies were described before (Liang et al, 2021). A half-hour prior to UV-radiation, the mice were pre-treated with different treatments as described above.…”

“…Mice were pretreated with T-CAR and empty transfersomes three times a week for two weeks before starting UV exposure. The UV treatment protocol was described before (Liang et al, 2021). In brief, the mice were irradiated with gradually increasing levels of UV three times a week for 25 weeks with an initial dose of 50 mJ/cm 2 that was increased each week by 25 mJ/cm 2 to 150 mJ/cm 2 , which was continued for the duration of the experiment.…”

“…The sections were stained with hematoxylin and eosin (H&E). The protocol for IHC was described in previous publication (Liang et al, 2021). The antibodies used are anti-COX-2 (1:600, Cell Signaling Technology, Danvers, MA, Cat no.…”