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Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cells
Author(s) -
Yang ShengHuei,
Chien ChingMing,
Su JungChen,
Chen YehLong,
Chang LongSen,
Lin ShinneRen
Publication year - 2008
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.20254
Subject(s) - k562 cells , stat protein , stat5 , cancer research , proto oncogene tyrosine protein kinase src , protein kinase b , chemistry , signal transduction , myeloid leukemia , cyclin d1 , janus kinase , downregulation and upregulation , apoptosis , microbiology and biotechnology , stat3 , biology , cell cycle , biochemistry , gene
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 antitumor agent in human leukemia cells. In the present study, treatment with IQDMA inhibited phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr‐Abl, and Janus‐activated kinase (JAK2) in a time‐dependent manner. IQDMA also degraded JAK2 protein. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling were also blocked by IQDMA. However, IQDMA did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt and extracellular signal‐regulated kinase 1/2. Furthermore, IQDMA upregulated the expression of p21 and p27 and downregulated the expression of cyclin D1, myeloid cell leukemia‐1(Mcl‐1), Bcl‐X L , and vascular endothelial growth factor (VEGF). Taken together, these results indicate that IQDMA causes significant induction of apoptosis in K562 cells via downregulation of EGFR, Src, Bcr‐Abl, JAK2, and STAT5 signaling and modulation of p21, p27, cyclin D1, Mcl‐1, Bcl‐X L , and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukemia K562 cells. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:396–404, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20254