Turning off transcription of the bcl-2 gene by stabilizing the bcl-2 promoter quadruplex with quindoline derivatives

J Med Chem. 2010 Jun 10;53(11):4390-8. doi: 10.1021/jm100445e.

Abstract

Human bcl-2 gene is an apoptosis-related oncogene containing a GC-rich sequence which is located upstream from P1 promoter and has the potential to form G-quadruplex structures. However, the regulatory role of the quadruplex and the effect of its ligands on bcl-2 have not been clarified. Here, we demonstrated that the G-quadruplex structure was disrupted when partial mutation of G --> A was made, resulting in a 2-fold increase in basal transcriptional activity of bcl-2 promoter. Quindoline derivatives, the highly active G-quadruplex ligands developed by our group, could significantly suppress bcl-2 transcriptional activation but had less effect on mutated bcl-2 transcription. These results provided direct evidence that G-quadruplex structure formed in bcl-2 promoter region could function as a transcriptional repressor element, and G-quadruplex specific ligands could regulate the transcription of bcl-2 through stabilization of quadruplex structure. The results further indicated that quindoline derivatives could induce apoptosis of HL-60 tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemistry*
  • Alkaloids / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Base Sequence
  • G-Quadruplexes / drug effects*
  • Genes, bcl-2 / genetics*
  • HL-60 Cells
  • Humans
  • Hydroxides / chemistry
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Ligands
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic / genetics*
  • Quinolines / chemistry*
  • Quinolines / pharmacology*
  • Thermodynamics
  • Transcription, Genetic / drug effects*

Substances

  • Alkaloids
  • Hydroxides
  • Indoles
  • Ligands
  • Quinolines
  • quindoline
  • hydroxide ion