A novel drug to treat advanced melanoma.

Abstract

e21000 Background: Advanced melanoma is a type of malignant skin cancer without effective treatment. Ginsenoside-Rg3 (Rg3), a saponin component extracted from ginseng roots, has been revealed to have an anti-cancer effect. However, there is limited data about its involvement in advanced melanoma. In this study, we investigated the role of Rg3 in melanoma by evaluating its in-vivo efficacy to inhibit melanoma growth, lung metastasis and melanoma-induced angiogenesis. We also revealed the potential underlying mechanisms by examining ERK and Akt pathways. Methods: 6-week-old C57BL/6 mice were purchased and maintained in our animal center. A highly metastatic subline of murine B16 melanoma cells was kindly provided by Dr. Xiaochun Xu, M.D. Anderson Cancer Center. Five groups were designed for this experiment: control (PBS), 3 groups with different doses of Rg3(0.3mg/kg, 1.0mg/kg, and 3.0mg/kg), and 5-FU (20mg/kg). 7 mice per group were given subcutaneous injection of 2 x 106 melanoma cells on the right flank for xenograft assay. 5 x 105 melanoma cells wrer subcutaneously injected on the right hind footpad for metastasis assay.The formed tumor tissues and lungs were collected for tumor growth and metastasis analysis, immunohistochemical staining, and western blotting. Results: For tumor growth, all the 3 Rg3 groups had smaller size of tumor and reduced expression of PCNA, a marker for cancer cell proliferation. For lung metastasis, the 3 Rg3 groups showed a lower number of tumor colonies with a dose-dependent manner. For angiogenesis, the 3 Rg3 groups displayed suppression of tumor-induced neovascularization through inhibition of VEGF. Western results demonstrated both ERK and Akt pathways were down-regulated in the Rg3 groups. Interestingly, immunohistochemical staining showed a higher number of CD8+ T cell in Rg3 groups lungs, suggesting immune response may be activated to fight against melanoma. Conclusions: Rg3 can decrease melanoma growth and metastasis by down-regulating ERK and Akt pathways. It may also inhibit melanoma metastasis by mediating VEGF-activated angiogenesis. More importantly, Rg3 may activate immune system to fight against advanced melanoma. Our study is the first to indicate Rg3 may be a promising novel drug for advanced melanoma. Based on these results, we are performing a clinical trial to test its efficacy to treat advanced melanoma.