PT  - JOURNAL ARTICLE
AU  - Sonja M Hampel
AU  - Antonella Pepe
AU  - Karin M Greulich-Bode
AU  - Sanjay V Malhotra
AU  - Anthony P Reszka
AU  - Sebastian Veith
AU  - Petra Boukamp
AU  - Stephen Neidle
TI  - Mechanism of the Anti-proliferative Activity of some Naphthalene Diimide G-quadruplex Ligands
AID  - 10.1124/mol.112.081075
DP  - 2012 Nov 27
TA  - Molecular Pharmacology
PG  - mol.112.081075
4099  - http://molpharm.aspetjournals.org/content/early/2012/11/27/mol.112.081075.short
4100  - http://molpharm.aspetjournals.org/content/early/2012/11/27/mol.112.081075.full
AB  - G-quadruplexes are higher-order nucleic acid structures which 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 down-regulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide (ND) ligands on the basis of cell biological data together with an NCI COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: a) telomere uncapping with subsequent DNA damage response and senescence, b) inhibition of transcription/translation of oncogenes, c) genomic instability though telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis and d) induction of chromosomal instability by telomere aggregate formation.