Involvement of c-Jun N-terminal kinase in G2/M arrest and FasL-mediated apoptosis induced by a novel indoloquinoline derivative, IQDMA, in K562 cells.
N'-(11H-Indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective anti-tumor agent in human leukemia cells. Treatment of K562 cells with IQDMA resulted in G2/M phase cell cycle arrest, presumably involving the concomitant up-regulation of p21 and apoptosis through up-regulation of FasL and sequential activation of caspase-8 and caspase-3. In contrast to the lack of appreciable effect on the phosphorylation of ERK and p38 MAPK, activation of JNK was noted when K562 cells were exposed to IQDMA. Moreover, IQDMA-mediated G2/M phase arrest and apoptosis were reversed after treatment with the JNK-specific inhibitors, SP600125 and JNK inhibitor 1. Further investigation showed that SP600125 reduced the activation of FasL, caspase-3, caspase-8, and led to a marked decline of p21. Taken together, our data show that JNK plays an important role in IQDMA-mediated G2/M arrest and apoptosis of K562 cancer cells.
Yang
Sheng-Huei
SH
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC.
Chien
Ching-Ming
CM
Lu
Chih-Ming
CM
Chen
Yeh-Long
YL
Chang
Long-Sen
LS
Lin
Shinne-Ren
SR
D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007938:Leukemia / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
D000873:Anthracenes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007211:Indoles; C524250:N'-(11H-indolo(3,2-c)quinolin-6-yl)-N,N-dimethylethane-1,2-diamine; D011804:Quinolines; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases