Harvard Medical School, BIDMC, Departmentof Matrix Biology, Boston, MA 02215, USA.
Anticancer Res. 2009 Nov;29(11):4559-70.
Tumor cells are resistant against apoptosis-inducing intercellular reactive oxygen species (ROS) signaling but can be resensitized by the inhibition of catalase. Hydrogen peroxide exhibits a dual role in the modulation of intercellular ROS signaling. When suboptimal concentrations of the catalase inhibitior 3-aminotriazole (3-AT) are applied, additional exogenous hydrogen peroxide shifts apoptosis induction to its optimum. When hydrogen peroxide is added at optimal concentrations of 3-AT, or when higher concentrations of 3-AT are applied, the subsequent consumption between HOCl and hydrogen peroxide blunts overall apoptosis induction. These supraoptimal conditions can be brought back to the optimum through excess myeloperoxidase (MPO), partial removal of hydrogen peroxide through the catalase mimetic EUK-134 or partial inhibition of NADPH oxidase. Exogenous nitric oxide (NO) interferes with HOCl signaling through consumption of hydrogen peroxide. Site-specific generation of hydroxyl radicals at the cell membrane of tumor cells induces apoptosis, whereas random HOCl-superoxide anion interaction, and ferrous iron-induced Fenton chemistry of HOCl inhibit intercellular ROS signaling.
肿瘤细胞对诱导细胞间活性氧物种 (ROS) 凋亡的信号具有抗性，但可以通过抑制过氧化氢酶来重新敏感化。过氧化氢在调节细胞间 ROS 信号中具有双重作用。当应用过氧化氢酶抑制剂 3-氨基三唑 (3-AT) 的亚最佳浓度时，额外的外源性过氧化氢将凋亡诱导转移到最佳状态。当在 3-AT 的最佳浓度下添加过氧化氢，或者当应用更高浓度的 3-AT 时，HOCl 和过氧化氢之间的后续消耗会使整体凋亡诱导变钝。通过过氧化物酶 (MPO) 的过量、通过过氧化氢模拟物 EUK-134 部分去除过氧化氢或部分抑制 NADPH 氧化酶，可以将这些超最佳条件恢复到最佳状态。外源性一氧化氮 (NO) 通过消耗过氧化氢来干扰 HOCl 信号。在肿瘤细胞膜上特异性生成羟基自由基诱导细胞凋亡，而 HOCl-超氧阴离子的随机相互作用和亚铁诱导的 HOCl 的 Fenton 化学则抑制细胞间 ROS 信号。
