Metal-based inhibition of poly(ADP-ribose) polymerase--the guardian angel of DNA.

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.

• Authors: Filipa Mendes, Michael Groessl, Alexey A Nazarov, Yury O Tsybin, Gianni Sava, Isabel Santos, Paul J Dyson, Angela Casini
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 7 Pg. 2196-206 (Apr 14 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21370912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Metals, Heavy
• Poly(ADP-ribose) Polymerase Inhibitors
• DNA
• Poly(ADP-ribose) Polymerases

Topics

• Amino Acid Sequence
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA (metabolism)
• Enzyme Inhibitors (chemistry, metabolism, pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• Inhibitory Concentration 50
• Metals, Heavy (chemistry, metabolism, pharmacology)
• Models, Molecular
• Molecular Sequence Data
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (chemistry, metabolism)
• Zinc Fingers