Byrnes R W, Mohan M, Antholine W E, Xu R X, Petering D H
Department of Chemistry, University of Wisconsin, Milwaukee 53201.
Biochemistry. 1990 Jul 31;29(30):7046-53. doi: 10.1021/bi00482a014.
Copper thiosemicarbazones cause considerable oxidative stress. This effect may be related to their cytotoxicity. In the present work, the chemical and cellular properties of a new ligand, pyridoxal thiosemicarbazone (H2T), and its copper(II) chelate (CuT) are assessed. CuT is toxic to cultured Ehrlich ascites tumor cells, producing nearly complete cell kill at drug/cell ratios of 2.5-4 nmol/10(5) cells in a monolayer culture over a 48-h treatment period. This concentration is at least 1 order of magnitude lower than those required for a similar degree of cytotoxicity by H2T or CuCl2. The following observations support the view that activated oxygen species are generated by interaction of CuT with Ehrlich cells: (1) Room-temperature electron spin resonance spectroscopy and atomic absorption measurements show rapid cellular uptake and CuT-thiol adduct formation. (2) Cellular thiol content is reduced. (3) High levels of DNA strand scission result from 1-h treatments of cells by concentrations of CuT that cause growth inhibition and toxicity. (4) The extent of strand scission can be increased by addition of superoxide dismutase and decreased by catalase or DMSO in the treatment medium. Catalase and DMSO do not inhibit the toxic effect of CuT. This suggests that DNA damage is not responsible for inhibition of cell proliferation by CuT.
硫代氨基脲铜会引起相当程度的氧化应激。这种效应可能与其细胞毒性有关。在本研究中，对一种新配体吡哆醛硫代氨基脲（H2T）及其铜（II）螯合物（CuT）的化学和细胞特性进行了评估。CuT对培养的艾氏腹水瘤细胞有毒性，在单层培养中，经过48小时的处理，当药物/细胞比例为2.5 - 4 nmol/10(5)细胞时，几乎能使细胞全部死亡。该浓度比H2T或CuCl2产生类似程度细胞毒性所需的浓度至少低1个数量级。以下观察结果支持了CuT与艾氏细胞相互作用产生活性氧的观点：（1）室温电子自旋共振光谱和原子吸收测量表明细胞能快速摄取CuT并形成CuT - 硫醇加合物。（2）细胞内硫醇含量降低。（3）用能导致生长抑制和毒性的CuT浓度处理细胞1小时会导致高水平的DNA链断裂。（4）在处理培养基中添加超氧化物歧化酶可增加链断裂程度，而添加过氧化氢酶或二甲基亚砜则可降低链断裂程度。过氧化氢酶和二甲基亚砜并不抑制CuT的毒性作用。这表明DNA损伤并非CuT抑制细胞增殖的原因。
