Mechanism of the antiproliferative activity of some naphthalene diimide G-quadruplex ligands

Sonja M. Hampel, Antonella Pepe, Karin M. Greulich-Bode, Sanjay V. Malhotra, Anthony P. Reszka, Sebastian Veith, Petra Boukamp, Stephen Neidle

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

G-quadruplexes are higher-order nucleic acid structures that can form in G-rich telomeres and promoter regions of oncogenes. Telomeric quadruplex stabilization by small molecules can lead to telomere uncapping, followed by DNA damage response and senescence, as well as chromosomal fusions leading to deregulation of mitosis, followed by apoptosis and downregulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide ligands on the basis of cell biologic data together with a National Cancer Institute COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: 1) telomere uncapping with subsequent DNA damage response and senescence; 2) inhibition of transcription/translation of onco-genes; 3) genomic instability through telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis; and 4) induction of chromosomal instability by telomere aggregate formation.

Original languageEnglish (US)
Pages (from-to)470-480
Number of pages11
JournalMolecular pharmacology
Volume83
Issue number2
DOIs
StatePublished - Feb 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Mechanism of the antiproliferative activity of some naphthalene diimide G-quadruplex ligands'. Together they form a unique fingerprint.

Cite this