Poly(ADP-ribose) glycohydrolase inhibitor as chemosensitiser of malignant melanoma for temozolomide.
Disruption of poly(ADP-ribose) polymerase (PARP) pathways by inhibitors of PARP catalytic domain has been shown to increase the anti-tumour activity of temozolomide (TMZ). Since PARP is inhibited by poly(ADP)ribosylation, herein we tested whether inhibition of poly(ADP-ribose) glycohydrolase (PARG) might enhance TMZ efficacy. The PARG inhibitor N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide (GPI 16552) was administered in combination with TMZ to mice injected subcutaneously or intracranially with B16 melanoma cells. The ability of treatment to reduce melanoma metastatic spreading and invasion of the extracellular matrix was also tested. The results indicated that combined treatment with GPI 16552 and TMZ significantly reduced melanoma growth, increased life-span of mice bearing tumour at the CNS site, and decreased the ability of melanoma cells to form lung metastases and to invade the extracellular matrix. In conclusion, PARG inhibition represents an alternative strategy to enhance TMZ efficacy against melanoma in peripheral as well as at CNS site.
Tentori
Lucio
L
Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Leonetti
Carlo
C
Scarsella
Marco
M
Muzi
Alessia
A
Vergati
Matteo
M
Forini
Olindo
O
Lacal
Pedro Miguel
PM
Ruffini
Federica
F
Gold
Barry
B
Li
Weixing
W
Zhang
Jie
J
Graziani
Grazia
G
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D005449:Fluorenes / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077204:Temozolomide
D005449:Fluorenes; C502402:N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide; D003606:Dacarbazine; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase; D000077204:Temozolomide