Institute of Inorganic Chemistry, University of Vienna, Austria.
J Biol Inorg Chem. 2011 Dec;16(8):1205-15. doi: 10.1007/s00775-011-0809-4. Epub 2011 Jun 26.
Ascorbic acid has been previously discussed to have antitumor potential through its interaction with transition metal ions such as iron and copper. Furthermore, ascorbic acid may act as a reducing agent for Ru(III) compounds such as indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019), an investigational anticancer drug which is supposed to be activated by reduction, prior to binding to cellular target proteins. Therefore, we investigated the influence of ascorbic acid on the activity of this antitumor metal complex in cell culture studies. We show that co-incubation of equicytotoxic, constant amounts of KP1019 with high concentrations of ascorbic acid (50-700 μM) increases cytotoxicity of the ruthenium anticancer drug in the human colon carcinoma cell line SW480, human cervical carcinoma KB-3-1 cells, and the multidrug-resistant subline KBC-1, whereas addition of low concentrations (2.7-50 μM) has a strong chemoprotective effect in the human colon carcinoma cell line SW480, but not in multidrug-resistant KBC-1 cells. Although cellular uptake of KP1019 is not altered, ascorbic acid induce stronger interaction of the ruthenium compound with DNA both in SW480 cells and under cell-free conditions with plasmid DNA. Even if DNA interactions probably play a subordinate role in vivo given the extensive protein binding of the compound, our data exemplify that ascorbic acid enhances the reactivity of KP1019 with biomolecules. Moreover, we demonstrate that the levels of KP1019-generated reactive oxygen species are markedly decreased by co-incubation with ascorbic acid. Conclusively, our results indicate that application of high doses of ascorbic acid might increase the anticancer effects of KP1019.
抗坏血酸先前被讨论通过与过渡金属离子如铁和铜相互作用而具有抗肿瘤潜力。此外，抗坏血酸可能作为还原试剂，用于[四氯双（1H-吲唑）合钌（III）]（KP1019）等 Ru（III）化合物，这是一种研究中的抗癌药物，预计通过还原被激活，然后再与细胞靶蛋白结合。因此，我们研究了抗坏血酸对该抗肿瘤金属配合物在细胞培养研究中的活性的影响。我们表明，与人结肠癌细胞系 SW480、人宫颈癌细胞 KB-3-1 细胞和多药耐药亚系 KBC-1 共孵育等细胞毒性，恒定数量的 KP1019 与高浓度抗坏血酸（50-700μM）一起孵育，增加了顺铂类抗癌药物的细胞毒性，而添加低浓度（2.7-50μM）对人结肠癌细胞系 SW480 具有强烈的化学保护作用，但对多药耐药 KBC-1 细胞则没有。尽管细胞摄取 KP1019 没有改变，但抗坏血酸在 SW480 细胞中和无细胞条件下与质粒 DNA 都诱导该钌化合物与 DNA 更强的相互作用。即使 DNA 相互作用在体内可能由于该化合物的广泛蛋白质结合而发挥次要作用，我们的数据例证了抗坏血酸增强了 KP1019 与生物分子的反应性。此外，我们证明，与抗坏血酸共孵育可使 KP1019 产生的活性氧物质的水平显著降低。总之，我们的结果表明，应用高剂量的抗坏血酸可能会增加 KP1019 的抗癌效果。
