Readers may remember a study from earlier this year that suggested that taking antioxidants canceled out some of the benefits of exercise. It seems that the reactive oxygen species themselves, which everyone’s been assuming have to be fought, are actually being used to signal the body’s metabolic changes.

Now there’s another disturbing paper on a possible unintended effect of antioxidant therapy. Joan Brugge and her group at Harvard published last month on what happens to cells when they’re detached from their normal environment. What’s supposed to happen, everyone thought, is apoptosis, programmed cell death. Apoptosis, in fact, is supposed to be triggered most of the time when a cell detects that something has gone seriously wrong with its normal processes, and being detached from its normal signaling environment (and its normal blood supply) definitely qualifies. But cancer cells manage to dodge that difficulty, and since it’s known that they also get around other apoptosis signals, it made sense that this was happening here, too.

But there have been some recent reports that cast doubt on apoptosis being the only route for detached cell death. This latest study confirms that, but goes on to a surprise. When this team blocked apoptotic processes, detached cells died anyway. A closer look suggested that the reason was, basically, starvation. The cells were deprived of nutrients after being dislocated, ran out of glucose, and that was that. This process could be stopped, though, if a known oncogene involved in glucose uptake (ERBB2) was activated, which suggests that one way a cancer cells survive their travels is by keeping their fuel supply going.

So far, so good – this all fits in well with what we already know about tumor cells. But this study found that there was another way to keep detached cells from dying: give them antioxidants. (They used either N-acetylcysteine or a water-soluble Vitamin E derivative). It appears that oxidative stress is one thing that’s helping to kill off wandering cells. On top of this effect, reactive oxygen species also seem to be inhibiting another possible energy source, fatty acid oxidation. Take away the reactive oxygen species, and the cells are suddenly under less pressure and have access to a new food source. (Here’s a commentary in Nature that goes over all this in more detail, and here’s one from The Scientist).

They went on to use some good fluorescence microscopy techniques to show that these differences in reactive oxygen species are found in tumor cell cultures. There are notable metabolic differences between the outer cells of a cultured tumor growth and its inner cells (the ones that can’t get so much glucose), but that difference can be smoothed out by. . .antioxidants. The normal process is for the central cells in such growths to eventually die off (luminal clearance), but antioxidant treatment kept this from happening. Even more alarmingly, they showed that tumor cells expressing various oncogenes colonized an in vitro cell growth matrix much more effectively in the presence of antioxidants as well.

This looks like a very strong paper to me; there’s a lot of work in it and a lot of information. Taken together, these results suggest a number of immediate questions. Is there something that shuts down normal glucose uptake when a cell is detached, and is this another general cell-suicide mechanism? How exactly does oxidative stress keep these cells from using their fatty acid oxidation pathway? (And how does that relate to normally positioned cells, in which fatty acid oxidation is actually supposed to kick in when glucose supplies go down?)

The biggest questions, though, are the most immediate: first, does it make any sense at all to give antioxidants to cancer patients? Right now, I’d very much have to wonder. And second, could taking antioxidants actually have a long-term cancer-promoting effect under normal conditions? I’d very much like to know that one, and so would a lot of other people.

After this and that exercise study, I’m honestly starting to think that oxidative stress has been getting an undeserved bad press over the years. Have we had things totally turned around?