Poly(ADP-ribose) glycohydrolase inhibitor as chemosensitiser of malignant melanoma for temozolomide

Lucio Tentori, Carlo Leonetti, Marco Scarsella, Alessia Muzi, Matteo Vergati, Olindo Forini, Pedro Miguel Lacal, Federica Ruffini, Barry Gold, Weixing Li, Jie Zhang, Grazia Graziani

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2948-2957
Number of pages10
JournalEuropean Journal of Cancer
Volume41
Issue number18
DOIs
Publication statusPublished - Dec 2005

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Keywords

  • (ADP-ribose) polymers
  • Blood-brain barrier
  • Brain tumours
  • Cancer
  • Metastasis
  • Poly(ADP-ribose) glycohydrolase
  • Poly(ADP-ribose) polymerase
  • Temozolomide

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

Tentori, L., Leonetti, C., Scarsella, M., Muzi, A., Vergati, M., Forini, O., Lacal, P. M., Ruffini, F., Gold, B., Li, W., Zhang, J., & Graziani, G. (2005). Poly(ADP-ribose) glycohydrolase inhibitor as chemosensitiser of malignant melanoma for temozolomide. European Journal of Cancer, 41(18), 2948-2957. https://doi.org/10.1016/j.ejca.2005.08.027