1Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona 60020, Italy
2Apoptosis Research Group, School of Medical Science, Griffith University Goald Coast Campus, Southport, Queensland 97726, Australia
3Molecular Therapy Group, Institute of Biotechnology, Academy of Sciences, Prague 14000, Czech Republic
4ARCES, University of Bologna, Bologna 40123, Italy
*Author for correspondence: Email: m.tomasetti/at/univpm.it
Revised February 12, 2010; Accepted February 23, 2010.
This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
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 α-tocopheryl succinate (α-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells.
Results:
Prostate cancer cells were sensitive to α-TOS and VK3 treatment, but resistant to AA upto 3.2
mM. When combined, a synergistic effect was found for VK3–AA, whereas α-TOS–VK3 and α-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 α-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.
mM. When combined, a synergistic effect was found for VK3–AA, whereas α-TOS–VK3 and α-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 α-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.
0 comments:
Post a Comment