title: Novel indoloquinoline derivative, IQDMA, suppresses STAT5 phosphorylation and induces apoptosis in HL-60 cells.
abstract: Signal transducers and activators of transcription (STATs) are a family proteins that mediate cytokine and growth factor-induced signals playing a role in cell differentiation, proliferation, angiogenesis, and apoptosis. One STAT family member, STAT5, is often constitutively active in myeloid leukaemia. Agents that can suppress STAT5 activation have potential for prevention and treatment of cancer. N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-dia-mine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective anti-tumor agent in human leukemia cells. In the present report, we tested IQDMA for its ability to suppress STAT5 activation. We found that IQDMA inhibited constitutive activation of STAT5 in HL-60 cells in a dose- and time-dependent manner. The activation of Src and interleukin-6 (IL-6), implicated in STAT5 activation, was also inhibited by the IQDMA. Furthermore, IQDMA up-regulated Bax, and down-regulated Bcl-2, Bcl-X(L), cyclin D1, and vascular endothelial growth factor (VEGF) as followed by growth arrest of HL-60 cells, but the expression of survivin did not change in the presence of IQDMA. Taken together, these results indicate that IQDMA causes significant induction of apoptosis in HL-60 cells via down-regulation of Src, IL-6, and STAT5 signaling and modulation of Bcl-2 family, cyclin D1 and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukaemia HL-60 cells.
authors.affiliation: Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC.
authors.forename: Ching-Ming
authors.initials: CM
authors.lastname: Chien
authors.forename: Sheng-Huei
authors.initials: SH
authors.lastname: Yang
authors.forename: Kuei-Li
authors.initials: KL
authors.lastname: Lin
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
authors.forename: Shinne-Ren
authors.initials: SR
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D007211:Indoles; D015850:Interleukin-6; C524250:N'-(11H-indolo(3,2-c)quinolin-6-yl)-N,N-dimethylethane-1,2-diamine; D011804:Quinolines; C108944:SOCS1 protein, human; D050799:STAT5 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019938:Cyclin D1; D016392:Proto-Oncogene Proteins pp60(c-src); C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6