Unknown

Dataset Information

0

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism.


ABSTRACT: 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.

SUBMITTER: Trachootham D 

PROVIDER: S-EPMC2518893 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

altmetric image

Publications

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism.

Trachootham Dunyaporn D   Zhang Hui H   Zhang Wan W   Feng Li L   Du Min M   Zhou Yan Y   Chen Zhao Z   Pelicano Helene H   Plunkett William W   Wierda William G WG   Keating Michael J MJ   Huang Peng P  

Blood 20080623 5


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-re  ...[more]

Similar Datasets

| S-EPMC3138741 | biostudies-literature
2013-09-21 | GSE51044 | GEO
| S-EPMC7316215 | biostudies-literature
| S-EPMC2064701 | biostudies-literature
2013-09-21 | E-GEOD-51044 | biostudies-arrayexpress
| S-EPMC4050125 | biostudies-literature
| S-EPMC3246489 | biostudies-literature
| S-EPMC1895341 | biostudies-literature
| S-EPMC3816211 | biostudies-literature
| S-EPMC6286670 | biostudies-literature