Trachootham Dunyaporn, Zhang Hui, Zhang Wan, Feng Li, Du Min, Zhou Yan, Chen Zhao, Pelicano Helene, Plunkett William, Wierda William G, Keating Michael J, Huang Peng
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 2008 Sep 1;112(5):1912-22. doi: 10.1182/blood-2008-04-149815. Epub 2008 Jun 23.
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 IC(50) values of 5.4 microM and 5.1 microM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC(50) = 27 microM, 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.
慢性淋巴细胞白血病（CLL）是最常见的成人白血病，对基于氟达拉滨的治疗产生耐药性是CLL治疗中的一项重大挑战。由于已知CLL细胞中活性氧（ROS）水平升高，我们旨在基于这种氧化还原改变测试一种新的ROS介导策略，以消除对氟达拉滨耐药的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，我们发现对氟达拉滨耐药和敏感的CLL细胞对β-苯乙基异硫氰酸酯（PEITC）均高度敏感，平均IC50值分别为5.4 microM和5.1 microM。正常淋巴细胞对PEITC的敏感性明显较低（IC50 = 27 microM，P <.001）。CLL细胞表现出内在的较高ROS水平和较低的细胞内谷胱甘肽，这被证明是CLL对PEITC敏感性的关键决定因素。将CLL细胞暴露于PEITC会导致严重的谷胱甘肽消耗、ROS积累以及线粒体心磷脂氧化，从而导致大量细胞死亡。这种ROS应激还会导致MCL1去谷胱甘肽化，随后该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可有效消除对氟达拉滨耐药的CLL细胞，且对正常淋巴细胞毒性低，值得进一步进行临床评估。
