Open AccessMolecular mechanisms of ZD1839 (Iressa)‐induced apoptosis in human leukemic U937 cells 1
Author(s) -
MOON Dongoh,
KIM Moonok,
LEE Jaedong,
CHOI Yunghyun,
LEE Minki,
KIM Giyoung
Publication year - 2007
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2007.00615.x
Subject(s) - protein kinase b , mapk/erk pathway , apoptosis , pi3k/akt/mtor pathway , microbiology and biotechnology , u937 cell , downregulation and upregulation , kinase , biology , signal transduction , chemistry , cancer research , biochemistry , gene
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‐2 H ‐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‐G 1 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.