Melanoma Cells Exposed to Clomiphene Citrate Respond With Cell Cycle Arrest and Reduced Invasiveness

Epidemiological studies have suggested that clomiphene citrate (CC) exposure may increase the risk of malignant melanoma, but mechanisms are unknown. We investigated the effects of CC on melanoma cell line A375. Cells were treated with CC at 2, 20, 200, and 2000 ng/mL, followed by assessment of cell viability and metabolism, cell cycle, migration, and expression of genes associated with epithelial–mesenchymal transition and mitochondrial oxidative stress. At 48 h, 2000‐ng/mL CC reduced cell viability by 80% ( p < 0.0001), induced early G1‐phase arrest ( p < 0.0001), and impaired cell migration. Gene expression analysis revealed decreased N‐cadherin/ CDH2 ( p < 0.05) and SOD2 ( p < 0.01) gene expression in the presence of CC, suggesting antimetastatic and prooxidant effects. These results indicate that direct exposure to CC does not promote aggressive melanoma cell behavior in vitro.