It’s hard to avoid hearing about all the health benefits of antioxidants: they prevent cancer, protect the cardiovascular system, enhance the immune system, reduce the risk of stroke... and the list goes on. Science journals are peppered with reports on the effects of antioxidants, methods of optimizing their levels in cooked, processed, and engineered foods, and boosting their levels in produce like apples. From the large volume of research, it’s clear that antioxidants do promote health, but a number of research groups have also described instances where antioxidants could be detrimental to health.

These instances mostly involve cancerous cells. Research groups have observed that increasing antioxidant capacity is associated with greater growth of breast cancer metastases in the brain. Researchers have questioned whether supplemental antioxidant use should be avoided during chemo and radiation therapy, as antioxidants appear to assist the abnormal overgrowth of cells in patients at risk to damaging chemicals, including those delivered by smoking, alcohol use, chemotherapy, or radiation treatments.

Antioxidants, evidently, are not exclusive to the type of cells that they assist. To better understand how antioxidants may promote tumors, researchers from Harvard, Johns Hopkins University, and the University of Notre Dame teamed up to take a deep look at their influence on tumor cell survival.

Zachary Schafer, the lead researcher, focused on epithelial cells, the most common source of cancers. Normally, epithelial cells die once they become displaced from the extracellular matrix, the mesh of proteins that supports and structures tissues. Tumor cells, in contrast, can detach from the extracellular matrix and proceed to multiply in the lumen between tissues. Somehow, the tumor cells find ways to survive on their own.

When Schafer and his colleagues examined the function of the extracellular matrix, they discovered that, in addition to its other roles, it regulated cellular metabolism. Detached mammary epithelial cells lost the ability to take up glucose, meaning less of it could be used to produce ATP, the cell's primary energy source.

Furthermore, displacement from the extracellular matrix led to a considerable increase in the levels of reactive oxygen species and a corresponding decrease in glutathione, an antioxidant produced by cells. The combination of ATP reduction and increased reactive oxygen species make it difficult for cells to survive independtly.

The authors were able to block the negative effects of matrix detachment when they expressed a cancer-promoting oncogene (ERBB2) in the epithelial cells. ERBB2 expression restored the cells' ability to take up glucose and reduced the levels of reactive oxygen species. So once again, the cells were able to produce ATP.

The connection between reactive oxygen species and ATP levels intrigued the researchers. They decided to treat detached cells with antioxidants to see if that alone would help the cells survive. They found that treating matrix-free cells with Trolox (a derivative of Vitamin E) or N-acetyl- L -cysteine (a widely used antioxidant) decreased reductive oxygen species, as expected.

But it also enhanced ATP levels in a manner that is entirely different from the action of oncogenes. Instead of restoring the cells' ability to take up glucose, antioxidants enhanced fatty acid oxidation, which is another metabolic method of generating ATP.

By delving into the biological basis by which antioxidants and oncogenes aid epithelial cell survival, Schafer and his collaborators have found that the two factors restore ATP production by different mechanisms. In the process, they also discovered that, while antioxidants protect our genetic material from mutations, they also support tumorgenesis by correcting metabolic problems. These dichotomous activities show us, once again, that biological processes are intricately interwoven, making it extremely difficult to strictly control the effects of any substance that we take.

Nature, 2009. DOI: 10.1038/nature08268

Listing image by National Cancer Institute