TY - JOUR
T1 - Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism
AU - Trachootham, Dunyaporn
AU - Zhang, Hui
AU - Zhang, Wan
AU - Feng, Li
AU - Du, Min
AU - Zhou, Yan
AU - Chen, Zhao
AU - Pelicano, Helene
AU - Plunkett, William
AU - Wierda, William G.
AU - Keating, Michael J.
AU - Huang, Peng
PY - 2008/9/1
Y1 - 2008/9/1
N2 - 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 β-phenylethyl isothiocyanate (PEITC) with mean IC 50 values of 5.4 μM and 5.1 μM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC50=27 μM, 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.
AB - 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 β-phenylethyl isothiocyanate (PEITC) with mean IC 50 values of 5.4 μM and 5.1 μM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC50=27 μM, 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.
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U2 - 10.1182/blood-2008-04-149815
DO - 10.1182/blood-2008-04-149815
M3 - Article
C2 - 18574029
AN - SCOPUS:52649153465
SN - 0006-4971
VL - 112
SP - 1912
EP - 1922
JO - Blood
JF - Blood
IS - 5
ER -