On the Mechanism of Synergistic Cytotoxicity of Vitamins C and K3: Experiments in Vitro and Quantum-Chemical Analysis

Abstract

Most patients with hepatocellular carcinoma are inoperable and hepatoma cells are resistant to conventional chemotherapies. So, it is important to develop novel therapies. Treatment of mouse hepatoma MH-22A cells by vitamins C and K3 at the ratio of 100:1 greatly enhanced their cytotoxicity. When cells were subjected to vitamin C at 200 μM or K3 at 2 μM separately, viability was more than 90%. However, when vitamins C and K3 were combined at these concentrations, less than 10% of cells survived.To elucidate the mechanism of this synergy, theoretical quantum-chemical analysis of the dynamics of intermolecular electron transfer (IET) processes within the complexes containing C and K3 was carried out. Optimization of the ground state complex geometry was provided by means of GAUSSIAN03 package. Simulation of the IET was done using NUVOLA package, in the framework of molecular orbitals. Rate of IET was calculated using Fermi Golden rule.Two concurrent pathways of a plausible mechanism of the synergistic action of vitamins C and K3 were analyzed: increasing of acidity in the near surrounding of complex significantly affects redox-cycling and creating the most stable [C2K] complex stabilizes acidity at a high level.Out of the complexes of vitamin K3 with five different forms of vitamin C, the most stable one was the complex with de-hydro-ascorbic acid [C2K], and the second one - with ascorbic acid [C1K]. The spectra of IET represent the different nature of complexes. There are several possibilities for electron transfer in the less stable [C1K] complex, while for the most stable [C2K] complex; the number of resonant states significantly decreases. This confirms that the creation of complex [C1K] escalates increasing of acidity.