Prevention of Skin Carcinogenesis by the Non-β-blocking R-carvedilol Enantiomer
Autor: | Kristan H. Cleveland, Abdullah Shamim, Sherry Liang, Ying Huang, Mengbing Chen, Cyrus Parsa, Bradley T. Andresen, Ayaz Shahid, Robert Orlando |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cancer Research Skin Neoplasms Carcinogenesis Ultraviolet Rays Inflammation Pharmacology medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine Skin Squamous Cell Carcinoma Animals Humans Medicine Neoplastic transformation Carvedilol Epidermal Growth Factor integumentary system business.industry Cancer Stereoisomerism Neoplasms Experimental medicine.disease HEK293 Cells 030104 developmental biology Epidermal Cells Oncology 030220 oncology & carcinogenesis Female Epidermis medicine.symptom Skin cancer Enantiomer business Oxidative stress medicine.drug |
Zdroj: | Cancer Prev Res (Phila) |
ISSN: | 1940-6215 1940-6207 |
Popis: | 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. Because 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 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/cm2 UV, topical treatment with R-carvedilol dose dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, and IL6 and IL1β 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. Prevention Relevance: In this study, we demonstrated the skin cancer preventive activity of R-carvedilol, the non-β-blocking enantiomer present in the racemic β-blocker, carvedilol. As R-carvedilol does not have β-blocking activity, such a preventive treatment would not lead to common cardiovascular side effects of β-blockers. |
Databáze: | OpenAIRE |
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