While many proponents of dietary antioxidants or supplements will claim they have incredible anticancer properties, amongst other things, the literature on these molecules is conflicting and animal and human studies of antioxidants as a potential cancer therapy have been largely disappointing. In fact, some trials have even found that antioxidant supplements can worsen some cancers. For example, vitamin E increases cancer burden and mortality in mouse models of lung cancer. This was particularly surprising since certain properties of cancer cells seemed to suggest that, in theory, they should be beneficial. The subject is therefore confusing and calls for much needed clarification.

In an attempt to address this issue, two researchers scoured the literature and came up with a hypothesis that may explain why these supplements are ineffective as a cancer therapy. The study has been published in The New England Journal of Medicine.

Their research is centered on the systems at play within cells that maintain a balance between oxidizing and anti-oxidizing molecules. These molecules are involved in so called redox reactions that involve the transfer of electrons from one agent to another. These reactions control certain cellular processes and also generate energy.

While oxidants are critical to cellular function, if they are produced in excess they can damage the cell. Cells produce natural antioxidants to prevent this from happening, but in cancer cells the balance is disrupted and high levels of these so called reactive oxygen species (ROS) are produced, promoting cancer. This is because ROS can cause genetic mutations and activate pathways that stimulate cell growth. It therefore seemed logical to conclude that antioxidants would thwart cancer progression, but that doesn’t seem to be the case.

The researchers suggest that this is because antioxidants from the diet or supplements aren’t getting to the right place in the cell, where ROS are produced and accumulate, rendering them useless. However, they note the successes of antioxidants that have been modified in such a way that they are targeted to a specific cellular location- the sausage-shaped energy factories called mitochondria.

They also propose a mechanism for the tumor-accelerating properties of dietary antioxidants. Certain cellular proteins that have tumor suppressive properties are actually activated by ROS; therefore decreasing ROS prevents their activation and subsequent action. Furthermore, some tumor promoting proteins are attenuated by ROS.

Interestingly, the levels of natural antioxidants are also boosted in cancer cells, which seems to be a mechanism to prevent uncontrolled damage by the high levels of ROS. They therefore suggest therapies designed to boost the levels of oxidants in cells could be beneficial. Indeed, radiotherapy and certain chemotherapies depend on ROS to kill the cells.

To conclude, the researchers suggest that inhibiting antioxidant proteins may be a useful strategy to combat cancer. Studies so far in rodent models of certain cancers have shown promise. The challenge that scientists are presented with is identifying antioxidants and pathways that are used by cancer cells, not normal cells. They therefore suggest that antioxidant profiling of tumor cells and neighboring normal cells may yield useful results that could ultimately help identify potential therapeutic targets.

[Via NEJM and CSHL]