PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy.
New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.
Salvati
E
E
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
Scarsella
M
M
Porru
M
M
Rizzo
A
A
Iachettini
S
S
Tentori
L
L
Graziani
G
G
D'Incalci
M
M
Stevens
M F G
MF
Orlandi
A
A
Passeri
D
D
Gilson
E
E
Zupi
G
G
Leonetti
C
C
Biroccio
A
A
D000166:Acridines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054856:G-Quadruplexes / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D016615:Telomere / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011065:Poly(ADP-ribose) Polymerases