Novel indoloquinoline derivative, IQDMA, induces G(2)/M phase arrest and apoptosis in A549 cells through JNK/p38 MAPK signaling activation.
OBJECTIVE
This study was performed to elucidate whether mitogen-activated protein kinases (MAPKs) are involved in the modulation of apoptosis and cell-cycle arrest by N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA), in human lung adenocarcinoma A549 cells.


METHODS
The effect of IQDMA on cell-cycle arrest and apoptosis was measured by flow cytometry, and phosphorylation levels of mitogen-activated protein kinases (MAPKs) and its regulatory molecules were studied by immunoblots.


RESULTS
IQDMA-induced G(2)/M arrest was associated with a marked decrease in the protein expressions of cyclin A, cyclin B, and cyclin-dependent kinase (Cdk)1. IQDMA-induced apoptosis was accompanied with up-regulation of the protein expression of Bax and down-regulation of the protein levels of Bcl-2, Mcl-1, X-linked inhibitor of apoptosis (XIAP), and survivin, resulting in cytochrome c release and sequential activation of caspase-9 and caspase-3. IQDMA activated c-Jun N-terminal kinase (JNK), p38 MAPK (p38) and extracellular signal-regulated kinase (ERK) on A549 cells in a time-dependent manner. Unlike the ERK inhibitor (PD98059), inhibitors of JNK (SP600125) and p38 MAPK (SB203580) suppressed IQDMA-induced apoptosis and G(2)/M phase arrest in A549 cells. Both SP600125 and SB203580 attenuated the activation of Bax and cytochrome c release, and reversed down-regulation of Bcl-2, XIAP, survivin, cyclin A, cyclin B, and Cdk1 in IQDMA-treated cells.


CONCLUSIONS
These findings indicate that JNK/p38 MAPK pathways play an important role in IQDMA-induced G(2)/M arrest and apoptosis of A549 cells.
Su
Jung-Chen
JC
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC.
Lin
Kuei-Li
KL
Chien
Ching-Ming
CM
Lu
Chih-Ming
CM
Chen
Yeh-Long
YL
Chang
Long-Sen
LS
Lin
Shinne-Ren
SR
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015394:Molecular Structure; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D007211:Indoles; C524250:N'-(11H-indolo(3,2-c)quinolin-6-yl)-N,N-dimethylethane-1,2-diamine; D011804:Quinolines; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases