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Summary Melanoma cells actively participate in tumor angiogenesis and vasculogenic mimicry. However, anti‐angiogenic therapy in patients with melanoma has not shown a significant survival gain. Thus, new anti‐melanoma angiogenic and vasculogenic drugs are highly desired. Using the metastatic melanoma cell line C8161 as a model, we explored melanoma vasculogenic inhibitors and found that lycorine hydrochloride (LH) effectively suppressed C8161 cell‐dominant formation of capillary‐like tubes in vitro and generation of tumor blood vessels in vivo with low toxicity. Mechanistic studies revealed that LH markedly hindered expression of VE‐cadherin in C8161 cells, but did not affect expression of six other important angiogenic and vasculogenic genes. Luciferase assays showed that LH significantly impeded promoter activity of the VE‐cadherin gene in a dose‐dependent manner. Together, these data suggest that LH inhibits melanoma C8161 cell‐dominant vasculogenic mimicry by reducing VE‐cadherin gene expression and diminishing cell surface exposure of the protein.

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