Hydroxyurea Kills Cells by Inducing the Production of Hydroxyl Radicals

Researchers have used a bacterial model system to explain the molecular mechanism by which the chemotherapeutic drug hydroxyurea kills cancer cells.

Investigators at the Massachusetts Institute of Technology (Cambridge, USA) and Boston University (MA, USA) employed the bacterium Escherichia coli as a model system to study the action of hydroxyurea.

In a paper published in the December 11, 2009, issue of the journal Molecular Cell they presented the results obtained by exposing E. coli to hydroxyurea. They found that hydroxyurea treatment rapidly induced a set of protective responses to manage DNA damage. Continued hydroxyurea stress activated iron uptake and the toxins MazF and RelE, whose activity caused the synthesis of incompletely translated proteins and stimulation of envelope stress responses. These effects altered the properties of one of the cell's terminal cytochrome oxidases, causing an increase in superoxide production. The increased superoxide production, together with the increased iron uptake, fueled the formation of hydroxyl radicals that contributed to hydroxyurea-induced cell death.

The hydroxyl radical has a very short in vivo half-life and is highly reactive. This makes it a very dangerous compound to the organism. Unlike superoxide, which can be detoxified by superoxide dismutase, the hydroxyl radical cannot be eliminated by an enzymatic reaction. It can damage virtually all types of macromolecules: carbohydrates, nucleic acids (mutations), lipids (lipid peroxidation), and amino acids. The only means to protect important cellular structures is the use of antioxidants such as glutathione and of effective repair systems.

Senior author Dr. Graham Walker, professor of biology at the Massachusetts Institute of Technology said, "This naturally leads to the thought that one could perhaps find a new class of antibiotic that acts further down the chain(s) of events that stimulate hydroxyl radical production."

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