Figure 1. Effects of nitrosylcobalamin (NO-Cbl), Apo2L/TRAIL, and their combination on the proliferation of melanoma cell lines A375, WM9, and WM3211 and normal cell lines CMN1, DMN1, and primary HFF fibroblasts. Left panels: Cells were treated with NO-Cbl (open bars), Apo2L/TRAIL (hatched bars), or pre-treated with NO-Cbl followed by Apo2L/TRAIL (solid bars) for three days, and growth was measured by the colorimetric sulforhodamine B assay (44). Data points represent the mean of four replicates±standard error of the mean (SEM). Right panels: Synergy between NO-Cbl and Apo2L/TRAIL was determined by median effect analysis (48), (combination index >1 indicates antagonism, =1 indicates additivity, and <1 indicates synergy). (a) The sequential treatment of NO-Cbl and Apo2L/TRAIL induced synergistic antiproliferative activity in A375, WM9 and WM3211 cells at each combined dose. (b) Normal melanocyte CMN1 and DMN1 cell lines, and normal HFF fibroblasts were completely resistant to simultaneous exposure to NO-Cbl, Apo2L/TRAIL, or the pre-treatment with NO-Cbl followed by Apo2L/TRAIL.