title: DNA strand cleavage by the phenazine di-N-oxide natural product myxin under both aerobic and anaerobic conditions.
abstract: Heterocyclic N-oxides are an interesting class of antitumor agents that selectively kill the hypoxic cells found in solid tumors. The hypoxia-selective activity of the lead compound in this class, tirapazamine, stems from its ability to undergo intracellular one-electron reduction to an oxygen-sensitive drug radical intermediate. In the presence of molecular oxygen, the radical intermediate is back-oxidized to the parent molecule. Under hypoxic conditions, the extended lifetime of the drug radical intermediate enables its conversion to a highly cytotoxic DNA-damaging intermediate via a "deoxygenative" mechanism involving the loss of oxygen from one of its N-oxide groups. The natural product myxin is a phenazine di-N-oxide that displays potent antibiotic activity against a variety of organisms under aerobic conditions. In light of the current view of heterocyclic N-oxides as agents that selectively operate under hypoxic conditions, it is striking that myxin was identified from Sorangium extracts based upon its antibiotic properties under aerobic conditions. Therefore, we set out to examine the molecular mechanisms underlying the biological activity of myxin. We find that myxin causes bioreductively activated, radical-mediated DNA strand cleavage under both aerobic and anaerobic conditions. Our evidence indicates that strand cleavage occurs via a deoxygenative metabolism. We show that myxin displays potent cytotoxicity against the human colorectal cancer cell line HCT-116 under both aerobic and anaerobic conditions that is comparable to the cell-killing properties of tirapazamine under anaerobic conditions. This work sheds light on the processes by which the naturally occurring aromatic N-oxide myxin gains its potent antibiotic properties under aerobic conditions. Furthermore, these studies highlight the general potential for aromatic N-oxides to undergo highly cytotoxic deoxygenative metabolism following enzymatic one-electron reduction under aerobic conditions.
authors.affiliation: Department of Chemistry, University of Missouri-Columbia, 125 Chemistry Building, Columbia, Missouri 65211, United States.
authors.forename: Goutam
authors.initials: G
authors.lastname: Chowdhury
authors.forename: Ujjal
authors.initials: U
authors.lastname: Sarkar
authors.forename: Susan
authors.initials: S
authors.lastname: Pullen
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: Anuruddha
authors.initials: A
authors.lastname: Rajapakse
authors.forename: Tarra
authors.initials: T
authors.lastname: Fuchs-Knotts
authors.forename: Kent S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000332:Aerobiosis; D000693:Anaerobiosis; D000970:Antineoplastic Agents / Q000633:toxicity; D001688:Biological Products / Q000138:chemical synthesis / Q000633:toxicity*; D045744:Cell Line, Tumor; D053837:DNA Cleavage; D006801:Humans; D010084:Oxidation-Reduction; D010619:Phenazines / Q000138:chemical synthesis / Q000633:toxicity; D000077704:Tirapazamine; D014227:Triazines / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D010619:Phenazines; D014227:Triazines; C005247:myxin; D000077704:Tirapazamine