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 3.2mM. 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.

M. Tomasetti, E. Strafella, S. Staffolani, L. Santarelli, J. Neuzil, R. Guerrieri (2010). a-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate. BRITISH JOURNAL OF CANCER, 102, 1224-1234 [10.1038/sj.bjc.6605617].

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

GUERRIERI, ROBERTO
2010

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 3.2mM. 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.
2010
M. Tomasetti, E. Strafella, S. Staffolani, L. Santarelli, J. Neuzil, R. Guerrieri (2010). a-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate. BRITISH JOURNAL OF CANCER, 102, 1224-1234 [10.1038/sj.bjc.6605617].
M. Tomasetti; E. Strafella; S. Staffolani; L. Santarelli; J. Neuzil; R. Guerrieri
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/88970
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