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.