Ascorbate Preferentially Stimulates Gallium-67 Uptake in Glioblastoma Cells

Gallium is a tri-valent p-block metal that closely mimics tri-valent iron. Gallium is internalized into cells via transferrin receptor-mediated endocytosis. Both Ga-67 and Ga-68 are radionuclides that can be radiolabeled to various bioactive compounds for clinical imaging procedures to visualize tumors and sites of inflammation. High-dose ascorbate (pharmacological ascorbate) is an emergent glioblastoma therapy that enhances cancer cell-killing through iron-metabolic perturbations. We hypothesized that pharmacological ascorbate treatments might alter Ga-67 uptake in glioblastoma cells. We evaluated the in vitro ability of pharmacological ascorbate to alter gallium uptake in patient-derived glioblastoma cells with variable genetic backgrounds by co-incubating cells with Ga-67 ± pharmacological ascorbate. Surprisingly, we observed increased basal gallium uptake in the glioblastoma cells compared to normal human astrocytes. Further, pharmacological ascorbate treatment stimulated gallium uptake in glioblastoma cells while not affecting uptake in normal human astrocytes. This effect appears to be related to transient increases in transferrin receptor expression. Finally, pharmacological ascorbate treatment appears to stimulate gallium uptake in an iron metabolism-dependent manner. Further mechanistic experiments are required to evaluate the translational utility of ascorbate to impact gallium tumor imaging.