α-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate

Abstract

Background: A strategy to reduce the secondary effects of anti-cancer agents is to potentiate the therapeutic effect by their combination. A combination of vitamin K3 (VK3) and ascorbic acid (AA) exhibited an anti-cancer synergistic effect, associated with extracellular production of H2O2 that promoted cell death. Methods: The redox-silent vitamin E analogue a-tocopheryl succinate (a-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells. Results: Prostate cancer cells were sensitive to a-TOS and VK3 treatment, but resistant to AA upto 3.2?mM. When combined, a synergistic effect was found for VK3-AA, whereas a-TOS-VK3 and a-TOS-AA combination showed an antagonist and additive effect, respectively. However, sub-lethal doses of AA-VK3 combination combined with a sub-toxic dose of a-TOS showed to induce efficient cell death that resembles autoschizis. Associated with this cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal-mitochondrial perturbation, and release of cytochrome c without caspase activation were observed. Inhibition of lysosomal proteases did not attenuate cell death induced by the combined agents. Furthermore, cell deaths by apoptosis and autoschizis were detected. Conclusion: These finding support the emerging idea that synergistic combinations of some agents can overcome toxicity and other side-effects associated with high doses of single drugs creating the opportunity for therapeutically relevant selectivity.