Inhibition of tumor growth and vasculogenic mimicry by cucumin through downregulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model

This study aims to investigate the underlying mechanism by which curcumin inhibits tumor growth and reduces vasculogenic mimicry (VM) in a murine choroidal melanoma model. Sixty mice were given subretinal injection with B16F10 cells and divided into a treatment and a control group. Curcumin was administered to the treatment group once a day at a dose of 100 mg/kg for 18 days starting at d3 (the day of inoculation is designated as d0); an equivalent volume of poloxamer-F68 was administered to the control group. Immunohistochemical and histochemical double staining were ued to detect the different blood supply patterns. The amounts of epithelial cell kinase (EphA2), phosphatidylinositol-3-kinase (PI3K) and matrixmetalloproteinase-2 and -9 (MMP-2, MMP-9) proteins expressed in the tumor tissue were analyzed using immunohistochemical staining; mRNA levels were measured using real-time PCR analysis. Results indicate that the tumor volume is reduced (p = 0.000) and that the numbers of VM (p = 0.000), mosaic vessels (p = 0.031) and endothelium-dependent vessels (p = 0.000) are significantly decreased by curcumin (p = 0.001). The expression levels of EphA2, PI3K, MMP-2 and -9 are also lower in the treatment group than in the control group (p = 0.001); similarly, mRNA levels in the treatment group are lower than those in the control group (p = 0.000). In conclusion, curcumin has the ability to inhibit the growth of engrafted melanoma VM channels through the regulation of vasculogenic factors that could be related to the downregulation of the EphA2/PI3K/MMPs signaling pathway. Thus, curcumin has the potential of being a clinical inhibitor of VM of choroidal melanoma.