Metal-Based Inhibition of Poly(ADP-ribose) Polymerase − The Guardian Angel of DNA

• Published in: Journal of medicinal chemistry Vol. 54; no. 7; pp. 2196 - 2206
• Main Authors: Mendes, Filipa, Groessl, Michael, Nazarov, Alexey A, Tsybin, Yury O, Sava, Gianni, Santos, Isabel, Dyson, Paul J, Casini, Angela
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.04.2011
• Subjects: Amino Acid Sequence; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; DNA - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Metals, Heavy - chemistry; Metals, Heavy - metabolism; Metals, Heavy - pharmacology; Models, Molecular; Molecular Sequence Data; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - chemistry; Poly(ADP-ribose) Polymerases - metabolism; Zinc Fingers
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2000135

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.