α-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate
MetadataShow full item record
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.
British Journal of Cancer
Copyright remains with the authors 2010. This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited. If you alter, transform, or build upon this work, you may distribute the resulting work only under a licence identical to this one.
Oncology and Carcinogenesis not elsewhere classified