@article{APS4349,
author = {Dong-oh Moon and Moon-ok Kim and Jae-dong Lee and Yung-hyun Choi and Min-ki Lee and Gi-young Kim},
title = {Molecular mechanisms of ZD1839 (Iressa)-induced apoptosis in human leukemic U937 cells},
journal = {Acta Pharmacologica Sinica},
volume = {28},
number = {8},
year = {2016},
keywords = {},
abstract = {Aim: To investigate the molecular mechanisms of ZD1839-induced apoptosis in human leukemic U937 cells.
Methods: The inhibition of human leukemic U937 cell growth was assessed by 3- (4, 5-dimethyl-2-thiazolyl)-2, 5-diphnyl-2H-tetrazolim bromide (MTT) assays, lactate dehydrogenase (LDH) release, and cell cycle distribution. The expression of anti- and pro-apoptotic proteins was detected by Western blot analysis.
Results: This study demonstrated that ZD1839 induced apoptosis in leukemic U937 cells by the downregulation of Bcl-2, caspase activation and subsequent apoptotic features. Cotreatment with ZD1839 and the caspase-3 inhibitor z-DEVD-fmk blocked apoptosis, indicating that caspase-3 activation is at least partially responsible for ZD1839-induced apoptosis. The ectopic expression of Bcl-2 attenuated caspase-3 activation, PARP cleavage, and subsequent indicators of apoptosis, including sub-G1 DNA content and LDH release. These results indicate that the downregulation of Bcl-2 plays a major role in the initiation of ZD1839-induced apoptosis, and that the activation of a caspase cascade is involved in the execution of apoptosis. Furthermore, ZD1839 treatment triggered the activation of p38 mitogen-activated protein kinase (MAPK) and the down-regulation of c-Jun-N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and phosphatidyl inositol 3-kinase (P13K)/Akt. The inhibition of the ERK and P13K/Akt pathways also significantly increased cellular death.
Conclusion: ZD 1839 activated caspase-3 and the inhibited Bcl-2 in human leukemic U937 cells through the downregulation of the ERK and P13K/Akt pathways.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/4349}
}