Wang Xiu-Fang, Witting Paul K, Salvatore Brian A, Neuzil Jiri
Apoptosis Research Group, School of Health Science, Griffith University, Southport, Qld, Australia.
Biochem Biophys Res Commun. 2005 Jan 14;326(2):282-9. doi: 10.1016/j.bbrc.2004.11.028.
Alpha-tocopheryl succinate (alpha-TOS) is a redox-silent vitamin E (VE) analog with high pro-apoptotic and anti-neoplastic activity. Here we investigated whether alpha-TOS and several novel VE analogs kill breast cancer cells over-expressing the anti-apoptotic receptor protein HER2/erbB2. The agents induced apoptosis at comparable levels in both erbB2-low and -high cells. Generation of reactive oxygen species (ROS) preceded mitochondrial destabilization and execution of apoptosis, as evidenced by the anti-apoptotic effects of exogenous superoxide dismutase and mitochondrially targeted coenzyme Q. Dissipation of DeltaPsi(m) was followed by cytochrome c and Smac/Diablo re-localization and caspase-dependent cleavage of death substrate. A resistance to apoptosis for the corresponding rho(0) counterparts confirmed a critical dependency for mitochondria during the induction of apoptosis in breast cancer cells mediated by VE analogs and linked apoptosis to generation of radicals as judged by the delayed accumulation of ROS in the cybrid cell types. We conclude that alpha-TOS causes efficient apoptosis in breast cancer cells independent of their erbB2 status. Since erbB2 is frequently over-expressed in breast cancers and renders the neoplastic disease resistant to established treatment, our findings are of clinical interest.
琥珀酸α-生育酚（α-TOS）是一种具有高促凋亡和抗肿瘤活性的氧化还原沉默维生素E（VE）类似物。在此，我们研究了α-TOS和几种新型VE类似物是否能杀死过度表达抗凋亡受体蛋白HER2/erbB2的乳腺癌细胞。这些药物在erbB2低表达和高表达的细胞中诱导凋亡的水平相当。活性氧（ROS）的产生先于线粒体不稳定和凋亡的执行，外源性超氧化物歧化酶和线粒体靶向辅酶Q的抗凋亡作用证明了这一点。线粒体膜电位（ΔΨm）的耗散之后是细胞色素c和Smac/Diablo的重新定位以及死亡底物的半胱天冬酶依赖性切割。相应的ρ0细胞对凋亡具有抗性，这证实了在VE类似物介导的乳腺癌细胞凋亡诱导过程中线粒体的关键依赖性，并根据杂交细胞类型中ROS的延迟积累将凋亡与自由基的产生联系起来。我们得出结论，α-TOS可在乳腺癌细胞中有效诱导凋亡，而与它们的erbB2状态无关。由于erbB2在乳腺癌中经常过度表达并使肿瘤疾病对既定治疗产生抗性，我们的发现具有临床意义。
