Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism
Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism
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DOI：
10.1182/blood-2008-04-149815
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发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Huang, Peng
中科院分区：
文献类型：
--
作者：
Trachootham, Dunyaporn;Zhang, Hui;Huang, Peng
慢性淋巴细胞白血病（CLL）是最常见的成人白血病，对氟达拉滨类药物的耐药性是CLL治疗的主要挑战。由于已知CLL细胞具有升高的活性氧（ROS）水平，我们旨在测试一种新的ROS介导的策略，以消除基于这种氧化还原改变的氟达拉滨抗性CLL细胞。使用来自患者（n = 58）和健康受试者（n = 12）的原代CLL细胞和正常淋巴细胞，我们发现氟达拉滨耐药和敏感的CLL细胞对β -苯乙基异硫氰酸酯（PEITC）高度敏感，平均IC50值分别为5.4 μ M和5.1 μ M。正常淋巴细胞对PEITC的敏感性明显降低（IC50 = 27 μ M, P < 0.001）。CLL细胞表现出内在较高的ROS水平和较低的细胞谷胱甘肽，这被证明是CLL对PEITC敏感性的关键决定因素。CLL细胞暴露于PEITC诱导严重的谷胱甘肽耗竭、ROS积累和线粒体心磷脂氧化，导致大量细胞死亡。这种ROS应激也引起MCL1的去谷胱甘肽化，随后这种细胞存活分子迅速降解。我们的研究表明，天然化合物PEITC通过氧化还原介导的机制有效消除氟达拉滨耐药CLL细胞，对正常淋巴细胞毒性低，值得进一步的临床评估。
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Because CLL cells are known to have elevated levels of reactive oxygen species (ROS), we aimed to test a novel ROS-mediated strategy to eliminate fludarabine-resistant CLL cells based on this redox alteration. Using primary CLL cells and normal lymphocytes from patients (n = 58) and healthy subjects (n = 12), we showed that both fludarabine-resistant and -sensitive CLL cells were highly sensitive to beta-phenylethyl isothiocyanate (PEITC) with mean IC50 values of 5.4 mu M and 5.1 mu M, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC50 = 27 mu M, P < .001). CLL cells exhibited intrinsically higher ROS level and lower cellular glutathione, which were shown to be the critical determinants of CLL sensitivity to PEITC. Exposure of CLL cells to PEITC induced severe glutathione depletion, ROS accumulation, and oxidation of mitochondrial cardiolipin leading to massive cell death. Such ROS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survival molecule. Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation.