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Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines.

Abstract
Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells. N'-(10H-Indolo [3,2-b] quinolin-11-yl)-N, N-dimethyl-propane-1,3-diamine (SYUIQ-5), (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC(50) for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.
AuthorsJ-M Zhou, X-F Zhu, Y-J Lu, R Deng, Z-S Huang, Y-P Mei, Y Wang, W-L Huang, Z-C Liu, L-Q Gu, Y-X Zeng
JournalOncogene (Oncogene) Vol. 25 Issue 4 Pg. 503-11 (Jan 26 2006) ISSN: 0950-9232 [Print] England
PMID16170347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Alkaloids
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Indoles
  • Quinolines
  • Cyclin-Dependent Kinase Inhibitor p27
  • quindoline
  • Guanine
  • DNA
  • Telomerase
Topics
  • Alkaloids (pharmacology)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cellular Senescence (drug effects)
  • Cyclin-Dependent Kinase Inhibitor p16 (analysis)
  • Cyclin-Dependent Kinase Inhibitor p21 (analysis)
  • Cyclin-Dependent Kinase Inhibitor p27 (analysis)
  • DNA
  • G-Quadruplexes
  • Guanine (chemistry)
  • Humans
  • Indoles (pharmacology)
  • K562 Cells
  • Neoplasms (drug therapy, genetics)
  • Quinolines (pharmacology)
  • Telomerase (antagonists & inhibitors)
  • Telomere

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