Novel action of paclitaxel against cancer cells: Bystander effect mediated by reactive oxygen species
Novel action of paclitaxel against cancer cells: Bystander effect mediated by reactive oxygen species
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DOI：
10.1158/0008-5472.can-06-3914
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Huang, Peng
中科院分区：
文献类型：
--
作者：
Alexandre, Jerome;Hu, Yumin;Huang, Peng
在紫杉醇治疗的癌细胞中观察到活性氧（ROS）的产生，但其潜在机制和治疗意义仍不清楚。在目前的研究中，我们发现紫杉醇促进ROS的产生。增强与质膜相关的NADPH氧化酶（NOX）的活性。乳腺癌细胞的治疗导致增加的Rac 1，一种正调控蛋白的氮氧化物，到膜部分的易位。紫杉醇诱导的ROS产生迅速发生在药物暴露的几个小时内，与O-2（-）和H2 O2的积累主要在细胞外，而细胞内RCIS保持不变。重要的是，细胞外ROS的增加对未暴露于紫杉醇的旁观者癌细胞造成致命损伤，如使用共培养系统的两种不同方法所示，其中旁观者细胞通过荧光或放射性标记与紫杉醇处理的细胞区分开。在其他微管靶向药物长春新碱和泰索帝中也观察到这种细胞毒性旁观者效应，但在5-氟尿嘧啶或多柔比星中未观察到。CuZnSOD可将O-2（-）转化为H2 O2，而过氧化氢酶可消除H2 O2，从而增强了这种毒性旁观者效应。此外，紫杉醇能够诱导几乎完全抑制增殖的旁观者细胞在共培养系统中。我们的研究揭示了一种新的机制，紫杉醇诱导毒性旁观者效应，通过产生细胞外H2 O2从膜相关的NOX。这可能有助于紫杉醇的有效抗癌活性，并为改善这一重要药物的临床应用提供了新的依据。
Generation of reactive oxygen species (ROS) has been observed in cancer cells treated with paclitaxel, but the underlying mechanisms and therapeutic implications remain unclear. In the present study, we showed that paclitaxel promoted ROS generation through. enhancing the activity of NADPH oxidase (NOX) associated with plasma membranes. Treatment of breast cancer cells caused an increased translocation of Rac1, a positive regulatory protein of NOX, to the membrane fraction. The paclitaxel-induced ROS generation occurred rapidly within several hours of drug exposure, with O-2(-) and H2O2 accumulation mainly outside the cells while the intracellular RCIS remained unchanged. Importantly, the increase in extracellular ROS caused lethal damage to the bystander cancer cells not exposed to paclitaxel, as shown by two different methods using coculture systems where the bystander cells were differentiated from the paclitaxel-treated cells by fluorescent or radioactive labeling. This cytotoxic bystander effect was also observed with other microtubule-targeted agents vincristine and taxotere but not with 5-fluorouracil or doxorubicin. This toxic bystander effect was enhanced by CuZnSOD that converts O-2(-) to H2O2 and was abolished by a catalase that eliminates H2O2. Furthermore, paclitaxel was able to induce an almost complete inhibition of proliferation of the bystander cells in the coculture system. Our study revealed a novel mechanism by which paclitaxel induces toxic bystander effect through generation of extracellular H2O2 from the membrane-associated NOX. This may contribute to the potent anticancer activity of paclitaxel and provide a novel basis to improve the clinical use of this important drug.