Phenanthriplatin Acts As a Covalent Poison of Topoisomerase II Cleavage Complexes.

Abstract

Drugs capable of trapping topoisomerase II (Top2), an essential enzyme that cleaves DNA to remove naturally occurring knots and tangles, can serve as potent anticancer agents. The monofunctional platinum agent phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl](NO3), is shown here to trap Top2 in addition to its known modes of inhibition of DNA and RNA polymerases. Its potency therefore combines diverse modes of action by which phenanthriplatin kills cancer cells. The observation that phenanthriplatin can act as a Top2 poison highlights opportunities to design nonclassical platinum anticancer agents with this novel mechanism of action. Such complexes have the potential to overcome current limitations with chemotherapy, such as resistance, and to provide treatment options for cancers that do not respond well to classical agents. Covalent DNA-platinum lesions implicated in Top2 poisoning are distinctive from those generated by known therapeutic topoisomerase poisons, which typically exert their action by reversible binding at the interface of Top2-DNA cleavage complexes.

• Authors: Imogen A Riddell, Keli Agama, Ga Young Park, Yves Pommier, Stephen J Lippard
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 11 Issue 11 Pg. 2996-3001 (11 18 2016) ISSN: 1554-8937 [Electronic] United States
• PMID: 27648475 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Organoplatinum Compounds
• Phenanthridines
• Topoisomerase II Inhibitors
• phenanthriplatin

Topics

• Humans
• Hydrolysis
• Organoplatinum Compounds (pharmacology)
• Phenanthridines (pharmacology)
• Topoisomerase II Inhibitors (pharmacology)