This study evaluated Farnesiferol C (FC), a natural coumarin, as a potential topoisomerase IIα (TOP2A) inhibitor to enhance chemotherapy and ionising radiation (IR) efficacy in melanoma cells. Key targets were identified, followed by enrichment and gene expression analyses, and molecular docking and dynamics simulations. Upon extraction of FC from Ferula szowitsiana, cell treatment with FC, alone or combined with IR or temozolomide (TMZ), was performed, and viability and apoptosis were assessed. TOP2A emerged as a hub target, showing elevated expression in melanoma and a negative correlation with patient survival. Simulations demonstrated stable binding of FC at the ATP-binding site of TOP2A. Experimental data revealed selective cytotoxicity of FC on A375 melanoma cells (IC50: 76.9µM, SI: 4.97), sparing normal fibroblasts. Combination treatments with IR or TMZ further increased cytotoxicity and apoptosis. These findings suggest FC as a promising TOP2A inhibitor that potentiates the DNA damage effects of chemoradiotherapy in melanoma.

Keywords