title: Mechanism of the antiproliferative activity of some naphthalene diimide G-quadruplex ligands.
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 oncogenes; 3) genomic instability through telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis; and 4) induction of chromosomal instability by telomere aggregate formation.
authors.affiliation: School of Pharmacy, University College London, London, United Kingdom.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Hampel
authors.forename: Antonella
authors.initials: A
authors.lastname: Pepe
authors.forename: Karin M
authors.initials: KM
authors.lastname: Greulich-Bode
authors.forename: Sanjay V
authors.initials: SV
authors.lastname: Malhotra
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Reszka
authors.forename: Sebastian
authors.initials: S
authors.lastname: Veith
authors.forename: Petra
authors.initials: P
authors.lastname: Boukamp
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D054856:G-Quadruplexes; D006801:Humans; D007094:Imides / Q000494:pharmacology*; D008024:Ligands; D061986:MCF-7 Cells; D008938:Mitosis / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D009857:Oncogenes / Q000187:drug effects; D016615:Telomere / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007094:Imides; D008024:Ligands; D009281:Naphthalenes; C542131:naphthalenediimide; D004247:DNA