Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect.
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.
Salvati
Erica
E
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
Leonetti
Carlo
C
Rizzo
Angela
A
Scarsella
Marco
M
Mottolese
Marcella
M
Galati
Rossella
R
Sperduti
Isabella
I
Stevens
Malcolm F G
MF
D'Incalci
Maurizio
M
Blasco
Maria
M
Chiorino
Giovanna
G
Bauwens
Serge
S
Horard
Béatrice
B
Gilson
Eric
E
Stoppacciaro
Antonella
A
Zupi
Gabriella
G
Biroccio
Annamaria
A
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
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