Modulation of Metastatic Potential of B16F10 Melanoma Cells by Acivicin: Synergistic Action of Glutaminase and Potentiation of Cisplatin Cytotoxicity

Treatment for metastatic melanoma has mostly been unsatisfactory despite advances in ongoing medicalresearch. Here we investigated the role of acivicin, a glutamine analogue, singly and in combination with eitherE. coli glutaminase or cisplatin, on the growth, angiogenic activity and invasiveness of B16F10 cells in vitro andafter allografting in C57BL/6 mice. B16F10 melanoma colonization in the lungs of mice was measured bymonitoring colony counts. Host toxicity was assessed with reference to tumor bearing host’s weight andsurvivability. Acivicin promoted melanoma dormancy and reduced melanoma associated angiogenic factorslike VEGF level and vessel diameter. Acivicin in combination with glutaminase significantly suppressed tumorgrowth by 66.7% and increased life-span by 43.5% without host toxicity. Tumor VEGF content was significantlylowered by combination therapy as assessed by ELISA. Accelerated cytotoxicity, reduced invasion and enhancedapoptosis of melanoma cells were exhibited in vitro by combined than by single agent treatment. Moreover,invasion of melanoma cells through matrigel chambers was reduced in the presence of acivicin and glutaminasein combination. These findings support future studies of acivicin in combination with other anticancer agentsfor prevention of melanoma metastasis.