Standard cancer therapy is plagued by undesirable adverse side-effects, including toxicity to normal cells and evasion of immune surveillance. These drawbacks have fuelled efforts to develop new anti-cancer agents and additional and/or complementary strategies to inhibit cancer cell growth. These strategies include approaches such as cancer immunotherapy (Lu et al, 2002; Roberts et al, 2002), caloric restriction (Zhu et al, 1997); genetic manipulation (Koch et al, 2000); a concomitant increase of the therapeutic effect of anti-cancer drugs while reducing undesirable secondary effects (Buc-Calderon et al, 1989); or potentiation of the anti-tumour therapeutic effects of drugs by their combination (Uwagawa et al, 2009; Zahorowska et al, 2009; Beauchamp et al, 2009; Eichhorn et al, 2010). Drug combination is a promising strategy to overcome side-effects associated with high doses of single drugs (Keith et al, 2005; Lehár et al, 2009).
The combined action of ascorbic acid (AA) and vitamin K3 (VK3) has been reported to synergistically induce cell death in different cancers (De loecker et al, 1993; Verrax et al, 2005; Tareen et al, 2008). Oxidative stress generated by the ascorbate-driven quinone redox cycling kills tumour cells by a mechanism including glycolysis inhibition, loss of calcium homoeostasis, DNA damage, and altered activity of mitogen-activated protein kinases (MAPK). In this case, cell death involves necrosis rather than apoptosis or macroautophagy (Beck et al, 2009). Pharmacological doses of AA (>0.2
mM) are required to induce oxidation-dependent cytotoxicity both in vitro (Beck et al, 2009) and in vivo (Tareen et al, 2008). Cells convert ascorbate to the ascorbyl radical (A−) with concomitant formation of H2O2 in extracellular fluids (Chen et al, 2007), resulting in toxicity towards tumour cells (Rhee, 2006). However, this approach faces a possible complications in that the therapeutic synergy of the drug combination could be accompanied by deleterious side-effects, and by the possibility that the extracellular levels of H2O2 main drop below 1μM, at which concentration proliferation rather than cell death may be promoted (Rhee, 2006).
mM) are required to induce oxidation-dependent cytotoxicity both in vitro (Beck et al, 2009) and in vivo (Tareen et al, 2008). Cells convert ascorbate to the ascorbyl radical (A−) with concomitant formation of H2O2 in extracellular fluids (Chen et al, 2007), resulting in toxicity towards tumour cells (Rhee, 2006). However, this approach faces a possible complications in that the therapeutic synergy of the drug combination could be accompanied by deleterious side-effects, and by the possibility that the extracellular levels of H2O2 main drop below 1μM, at which concentration proliferation rather than cell death may be promoted (Rhee, 2006).To overcome these potential adverse effects, we have tested the hypothesis that cell death induced by an extracellular oxidative insult could be enhanced by combining apoptotic agents acting through different modes of action. One of the emerging targets for anti-cancer drugs is mitochondria that is central to induction of programmed cell death (Gogvadze et al, 2008; Trachootham et al, 2009). Our previous work has identified mitochondria as transmitters of apoptosis induced by the redox-silent analogue of vitamin E (VE) α-tocopheryl succinate (α-TOS) (Neuzil et al, 2004, 2007a) that is selective for cancer cells (Neuzil et al, 2001a, 2001b) and suppresses tumours in a variety of pre-clinical models (Neuzil et al, 2001b; Stapelberg et al, 2005; Wang et al, 2007; Dong et al, 2008, 2009). This suggests that the VE analogue is a promising anti-cancer drug that may suppress tumours by causing cell death of malignant cells as well as synergizing with other anti-cancer agents. In this study, we used the agent in combination with VK3 and AA stimulating the redox cycling system to evaluate their combined anti-cancer effects on one human prostate cancer cell line.
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