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UK Team Studies Whether RNAi Can Be Useful Antioxidant Tool

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Chasing antioxidants by eating broccoli or popping vitamin E pills may not be the only ways to help prevent disease. RNA interference could be another way to boost the body's defense against harmful oxidizing chemicals, according to a new paper by John Hayes, a professor at the University of Dundee in Scotland.

The paper, which appears in this week's early edition of The Proceedings of the National Academy of Sciences, shows that inhibiting the Keap1 gene in human skin cells can ramp up the expression of genes that protect cells from the damage caused by oxidants.

"What we did was not novel from an siRNA point of view," Hayes told RNAi News. "It was more the target that was important."

In the cell, a transcription factor called Nrf2 is responsible for switching on chemoprotective, or antioxidant, genes. Keap1, however, normally keeps Nrf2 in check by promoting its breakdown by the cell's proteasome. But Keap1 enables Nrf2 to do its job only if a cell is exposed to stress from oxidizing chemicals — a signal that it needs more antioxidants.

"The disadvantage with that mechanism is if you get a sudden exposure to nasty chemicals or reagents that deplete the antioxidants, it takes a period of time for the cell to react and mount a defense," Hayes said. "What we wanted to know is, under normal conditions, could we activate this system just by using siRNA to knock down the negative regulator, the Keap1 protein?"

As it turned out, they could: One of two duplex 21 nucleotide siRNAs, directed against Keap1 and designed by Cenix Bioscience in Dresden, was able to increase Nrf2 protein concentration in human keratinocyte cells. It also up-regulated a number of downstream antioxidant genes.

This answer was surprising, Hayes said, because researchers had assumed that in addition to removing Keap1, it would also be necessary to increase the concentration of oxidants to activate Nrf2 by some sort of phosphorylation event. "What our findings suggest is [that] you don't need a secondary activation mechanism — it's sufficient just to remove Keap1," Hayes said. "It suggests that Keap1 is a drug target."

In theory, Keap1 suppression could be used to prevent diseases linked to oxidants. People at higher risk of cancer through an inherited genetic predisposition or by exposure to carcinogens, through their occupation or diet, for example, could protect themselves. Moreover, Keap1 suppression might help to prevent degenerative diseases related to aging. "In old age, our antioxidant capacity is diminished," said Hayes. "So you could seek to augment it in this way."

The advantage of siRNA over using other cancer-preventing antioxidants, which occur, for example, in certain vegetables, is that it is more precise and will not stimulate multiple pathways, he said.

So far, Hayes has not explored commercial avenues yet or collaborated with any companies. Most of his funding comes from cancer charities, which are "aware of intellectual property or licensing," he said. "It's something that I would be interested in, but we haven't made any commitments as yet."

But the UK's Ministry of Defense, which provided part of the funding for the study, also has an interest in the research for potential anti-terrorism applications. One of the co-authors of the paper, Christopher Lindsay, works at the Defense Science and Technology Laboratory in Salisbury. "He came up with the idea of trying to use chemoprevention to protect against chemical weapons," Hayes said. "But it was at this end that we came up with the idea of using siRNA."

Next, Hayes' team plans to analyze which antioxidant genes get turned on by Nrf2 in human cells. In mice, about 200 genes are known to be regulated by the transcription factor. Preliminary experiments by Hayes suggest that in humans, this battery of genes is different.

The other question he wants to pursue, using cell-based models, is whether activating the Nrf2 system can protect human cells against certain types of cancer-causing chemicals.

But it will be many years before his approach can be tested in humans, he estimates. Provided funding from the Ministry of Defense comes through, his team would like to start experiments in rats within a year, testing different types of delivery systems.

— JK

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