Induction of CD95 ligand and apoptosis by doxorubicin is modulated by the redox state in chemosensitive- and drug-resistant tumor cells
Induction of CD95 ligand and apoptosis by doxorubicin is modulated by the redox state in chemosensitive- and drug-resistant tumor cells
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DOI：
10.1038/sj.cdd.4400512
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发表时间：
1999-05-01
影响因子：
12.4
通讯作者：
Debatin, KM
中科院分区：
文献类型：
--
作者：
Friesen, C;Fulda, S;Debatin, KM
在化疗敏感的白血病和实体瘤中，诱导CD 95配体（CD 95-L）可能有助于药物诱导的细胞凋亡。在此，我们报告了阿霉素诱导白血病和神经母细胞瘤细胞中的CD 95-L和细胞凋亡受氧化还原状态和活性氧（ROS）的调节。显著减少阿霉素诱导的细胞凋亡、ROS的过度表达、线粒体膜电位（Δ Psi（m））的损失和CD 95-L表达的上调。与化学敏感性细胞相比，多柔比星抗性细胞表现出更高水平的GSH，并且响应于细胞毒性药物而缺乏ROS的过度产生、Δ Psi（m）的损失和CD 95-L的上调。细胞内GSH浓度的下调逆转了药物诱导的ROS的过度产生和CD 95-L的上调。此外，Bcl-X-L在CEM细胞中的过表达阻断了阿霉素触发的ROS和CD 95-L的表达。这些发现表明细胞毒性药物对CD 95-L的诱导受细胞氧化还原状态和线粒体衍生的ROS调节。
Induction of CD95 ligand (CD95-L) may contribute to drug-induced apoptosis in chemosensitive leukemias and solid tumors, Here we report that induction of CD95-L and apoptosis by doxorubicin in leukemic and neuroblastoma cells is regulated by the redox state and reactive oxygen species (ROS), Preincubation of chemosensitive cells with antioxidants such as N-acetyl-cysteine (NAC) or glutathione (GSH), significantly reduced doxorubicin-induced apoptosis, hyperexpression of ROS, loss of mitochondrial membrane potential (Delta Psi(m)) and upregulation of CD95-L expression. Doxorubicin-resistant cells exhibited higher levels of GSH in comparison to chemosensitive cells and were deficient in hyperproduction of ROS, loss of Delta Psi(m) and upregulation of CD95-L in response to cytotoxic drugs, Downregulation of intracellular GSH concentrations reversed deficient drug-induced hyperproduction of ROS and CD95-L upregulation, In addition, overexpression of Bcl-X-L in CEM cells blocked doxorubicin-triggered ROS and CD95-L expression, These findings suggest that induction of CD95-L by cytotoxic drugs is modulated by the cellular redox state and mitochondria derived ROS.