Metformin – A New Frontier in Skin Cancer Pharmacotherapy

Metformin, a widely prescribed biguanide for type 2 diabetes, has emerged as a promising candidate in skin cancer therapy due to its diverse anticancer mechanisms. Beyond its glucoselowering effects, metformin inhibits key oncogenic pathways, including the PI3K/AKT/mTOR and insulin/IGF-1 signaling pathways, activates AMP-activated protein kinase, and disrupts mitochondrial complex I function. These mechanisms are presumed to contribute to metformin's antiproliferative, pro-apoptotic, and anti-inflammatory effects, potentially reducing tumor growth and metastasis in melanoma and non-melanoma skin cancers. Predictive molecular docking studies reveal that metformin interacts with critical proteins in melanoma pathophysiology. Against PI3K/mTOR (PDB: 5OQ4), PTPN2 (PDB: 7UAD), and TRIP13 (PDB: 5VQA), metformin exhibited docking scores of -4.4, -4.6, and -5.6 kcal/mol, respectively, interacting via hydrogen bonding with residues such as ASP-836, ASP-964 (5OQ4), ASP-50 (7UAD), and SER-187, SER-138 (5VQA). Compared to standard inhibitors, PQR309 (-9.4 kcal/mol), ABBV-CLS-484 (-7.5 kcal/mol), and ATP (-10.8 kcal/mol), metformin displayed moderate binding affinity, suggesting potential but weaker inhibition of these targets. Preclinical and clinical studies support metformin's potential to reduce skin cancer risk, particularly in diabetic patients. However, challenges regarding bioavailability, optimal dosing, and patient selection persist, necessitating further investigation. Therefore, given its affordability, safety, and multitargeted action, metformin represents an attractive candidate for repurposing in skin cancer pharmacotherapy. Focusing future research on optimizing its therapeutic application, refining drug combinations, and identifying biomarkers would enhance clinical outcomes.