Metal-based inhibition of poly(ADP-ribose) polymerase: The guardian angel of DNA

Filipa Mendes, Michael Groessl, Alexey A. Nazarov, Yury O. Tsybin, Gianni Sava, Isabel Santos, Paul J. Dyson, Angela Casini*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

118 Citations (Scopus)

Abstract

The inhibition activity of a series of anticancer metal complexes based on platinum, ruthenium, and gold metal ions was evaluated on the zinc-finger protein PARP-1, either purified or directly on protein extracts from human breast cancer MCF7 cells. Information on the reactivity of the metal complexes with the PARP-1 zinc-finger domain was obtained by high-resolution ESI FT-ICR mass spectrometry. An excellent correlation between PARP-1 inhibition in protein extracts and the ability of the complexes to bind to the zinc-finger motif (in competition with zinc) was established. The results support a model whereby displacement of zinc from the PARP-1 zinc finger by other metal ions leads to decreased PARP-1 activity. In vitro combination studies of cisplatin with NAMI-A and RAPTA-T on different cancer cell lines (MCF7, A2780, and A2780cisR) showed that, in some cases, a synergistic effect is in operation.

Original languageEnglish
Pages (from-to)2196-2206
Number of pages11
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
Publication statusPublished - 14-Apr-2011
Externally publishedYes

Keywords

  • ORGANOMETALLIC RUTHENIUM COMPOUND
  • PLATINUM-MODIFIED DNA
  • MASS-SPECTROMETRY
  • ANTICANCER DRUGS
  • SOLUTION CHEMISTRY
  • NUCLEAR PROTEINS
  • ZINC FINGERS
  • GOLD(III) COMPLEXES
  • BINDING PROPERTIES
  • BIPYRIDYL LIGANDS

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