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

Oncogene. 2006 Jan 26;25(4):503-11. doi: 10.1038/sj.onc.1209067.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Neoplasms / genetics
  • Quinolines / pharmacology*
  • Telomerase / antagonists & inhibitors
  • Telomere*

Substances

  • Alkaloids
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Indoles
  • Quinolines
  • Cyclin-Dependent Kinase Inhibitor p27
  • quindoline
  • Guanine
  • DNA
  • Telomerase