Study finds first evidence COX-2 enzymes can regulate DNA damage
Scientists from the University of Pennsylvania's Center for Cancer Pharmacology report the first evidence that cylcooxygenase-2 enzymes (known as COX-2) are not only responsible for pain and inflammation but that they are also involved in causing the DNA damage associated with cancer.
Dr. Ian Blair reports this study for the first time on June 15th at the Annual Meeting of the American Society for Biochemistry and Molecular Biology (ASBMB)/8th International Union of Biochemistry and Molecular Biology Conference (IUBMB) in Boston. His research team's discovery casts a new light on the mechanism through which aspirin - and diets rich in fruits, grain and vegetables -- appear to lower the risk of some cancers. It also suggests a potential role for the widely used COX-2 inhibitors in the prevention of DNA damage.
In the same presentation, Dr. Blair reports new data that support his earlier discovery that vitamin C can increase DNA damage. His 2001 article in Science was the first to report a potential negative effect of vitamin C and thus caused a firestorm of attention, although Dr. Blair was careful to spell out that he believed that in order to be at risk for DNA damage from vitamin C an individual would have to take some unknown high quantity of the vitamin, experience oxidative stress, and have a problem with the ordinarily efficient DNA repair enzymes. The two studies are closely related, says Dr. Blair, because the COX-2 enzyme produces lipid hydroperoxides and vitamin C stimulates their breakdown. This results in the formation of a class of DNA-harming agents called genotoxins, which are known to be involved in the formation of certain human cancers.
Interest in the potential use of COX-2 inhibitors as anticancer agents was fueled in part a decade ago when an American Cancer Society study showed that regular use of aspirin led to an unexpectedly low incidence of colon cancer. But all was not rosy. In addition to inhibiting the production of COX-2, aspirin also inhibits production of COX-1. These COX-1 enzymes make prostaglandins, regulatory molecules important for, among other things, preventing the formation of ulcers in the gastrointestinal tract.
But what if the culprit in the creation of genotoxins, and thus the real target of aspirin in preventing cancer, had nothing to do with prostaglandins and instead was actually some other product derived from COX-2? Ten years ago researchers at Vanderbilt Universitydemonstrated that COX-2 was present in colon tumors but not in surrounding healthy tissues. The Vanderbilt laboratory then developed a cellular model that introduced the COX-2 enzyme into cells to study the biochemical changes that occurred. In a spirit of scientific collegiality, the Vanderbilt group supplied Dr. Blair's lab their cellular model so that the University of Pennsylvania team could look at whether the COX-2 enzyme could produce the DNA-damaging genotoxins that the COX-1 enzyme was unable to make.
A new method was developed for the analysis of DNA damage in these cells at the University of Pennsylvania by Dr. Seon Hwa Lee, Research Associate in Pharmacology, and Ms. Michelle Williams, a student in the Graduate Group in Pharmacological Sciences. They found that in the cells COX-2 was able to make lipid hydroperoxides and that vitamin C could efficiently convert them into genotoxins.
Under normal circumstances, says Dr. Blair, oxidized hydroperoxide is rapidly removed from the cells before it would have time to degrade into genotoxins but under abnormal circumstances such as oxidative stress, degradation could take place.
Dr. Blair says these studies provide the first hint that COX-2 enzymes are responsible for DNA damage and that inhibition of this damage may be important for preventing cancer. He believes that the ability of COX-2 inhibitors to prevent genotoxin formation during cellular oxidative stress suggests a potential usefulness in cancer prevention and that new drugs could be developed to remove COX-2 derived cellular genotoxins.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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