Potential Application of Cocoa Extract in Preventing Skin Cancer Through Inhibition of Adenosine Receptor A2, VEGFR-2, and BCL-2: in vivo and Docking Molecular Studies

Objective: Skin cancer is a growing global health issue.Natural compounds with multi-pathway activity are promising chemopreventive agents.Cocoa extract contains bioactive components that may inhibit cancer-related molecular pathways, such as flavonoids, polyphenols, and alkaloids.This study aims to assess the chemopreventive potential of cocoa extract against skin cancer by targeting the adenosine A2 receptor and vascular endothelial growth factor receptor-2 (VEGFR-2), and by modulating B-cell lymphoma-2 (BCL-2) expression, using both in vivo and molecular docking methods.Methods: Thirty female Swiss mice were treated with (7,12-dimethylbenz[a] anthracene) and (12-O-tetradecanoylphorbol-13-acetate) to induce squamous cell carcinoma.Cocoa extract (1600 ppm) was administered as a preventive treatment for 12 weeks.Measurements included flavonoid and polyphenol content, malondialdehyde (MDA) levels, BCL-2 protein expression, and histopathological evaluation.Molecular docking was performed to assess interactions between cocoa compounds and adenosine A2 and VEGFR2 receptors. Results:The cocoa extract contained 118.72 µg of flavonoids and 66.24 mg of polyphenols.Theobromine inhibited adenosine A2 receptor activity and reduced interleukin-8 expression.Procyanidin and epicatechin bound to VEGFR2, potentially suppressing angiogenesis.Immunohistochemistry showed significant reductions in both BCL-2 expression (p=0.035) and MDA levels (p=0.001),indicating decreased oxidative stress.Histological analysis revealed milder dysplasia in the cocoa-treated group compared to controls (p=0.002).Conclusions: Cocoa extract demonstrates potential as a natural chemopreventive agent against skin cancer through antioxidant activity, anti-angiogenesis, and apoptosis modulation pathways.