Inhibition of SVCT1 Binding/Transport Dynamics as Possible Molecular Mechanisms of Lithium L-ascorbate Radiosensitization

Introduction: This study aimed to investigate a plausible mechanism underlying the potential radiosensitizing activity of lithium L-ascorbate by modelling lithium versus sodium effects in the binding pocket/pore of the sodium-dependent vitamin C transporter SVCT1 in silico. Researchers then conducted in vitro tests to determine if extracellular lithium effectively reduces the accumulation of ascorbate within cells. Methods: SVCT1 protein structures (PDB: 7YTW, 7YTY) were prepared, embedded in lipid membranes, and simulated using GROMACS with CHARMM36 force fields, comparing Na+ and Li+ ion effects on ascorbate transport over 100 ns. Jurkat cells were incubated with ascorbate (100 μM) and Li+ (0.5, 1, 2, and 4 mM) for 24 hours. Intracellular ascorbate levels were measured via stripping voltammetry on a carbon glass electrode. Results: Molecular simulations revealed that Li+ ions delay release from the SVCT1 pocket. It suggested altered ion residence and pore geometry consistent with impaired Na+-coupled ascorbate transport. In vitro experiments showed a significant reduction in intracellular ascorbate concentrations at media Li+ concentrations of 0.5-2 mM. Discussion: We hypothesized that lithium-ion inhibition of SVCT-mediated ascorbate uptake increased extracellular ROS formation. That highlights a potential ion-specific regulatory mechanism in cellular redox homeostasis. Conclusion: These findings support a transport-centered mechanism for lithium-induced radiosensitization, involving inhibition of SVCT1-dependent ascorbate transport. This effect likely promotes extracellular pro-oxidant conditions and oxidative stress, as previously demonstrated.