title: Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect.
abstract: Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors gamma-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.forename: Marco
authors.initials: M
authors.lastname: Scarsella
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Rossella
authors.initials: R
authors.lastname: Galati
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Malcolm F G
authors.initials: MF
authors.lastname: Stevens
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Maria
authors.initials: M
authors.lastname: Blasco
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.forename: Serge
authors.initials: S
authors.lastname: Bauwens
authors.forename: Béatrice
authors.initials: B
authors.lastname: Horard
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zupi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
mesh_terms: D000166:Acridines / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D054856:G-Quadruplexes; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C440849:POT1 protein, human; C113575:Rad17 protein, human; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C498301:TP53BP1 protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D000071857:Tumor Suppressor p53-Binding Protein 1; D004247:DNA; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases