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Antioxidants help cancer metastasize

Антиоксиданты помогают раку метастазировать
Breast cancer cell. (Photo Visuals Unlimited / Corbis.)

Diabetes medications that reduce the level of oxidative stress, thereby pushing cancer tumors to metastasize.

It is known that oxygen radicals - the so-called special molecules, which include oxygen and which have a very high oxidative activity due to an unpaired electron - can greatly harm DNA.

When there are a lot of such radicals, oxidative stress arises, and the cell can either just die from mutations, or, say, give rise to a cancerous tumor. Highly active oxygen oxidants are obtained as a by-product of some important cellular processes, so that during the course of evolution, living beings had the tools to neutralize them.

Антиоксиданты помогают раку метастазировать
Lung cancer cells in the lymph node. (Photo by NCI / PHANIE / phanie / Phanie Sarl / Corbis.)

However, built-in antioxidant protection systems may not cope with the problem - and then they can be helped by eating some antioxidant drug.

But after all, cancer cells, since they have already appeared, oxidative stress is not needed at all. If a cancer badly spoils the DNA, no matter how malignant the tumor is, it will die anyway - in fact, the mass of anti-cancer drugs does exactly that, which causes mutations in the DNA of the tumor cells. Then it turns out that antioxidants play on the hand of cancer, saving its genes from damage. It was this logic in the reasoning of James Watson (we recall one of the legendary authors of the double-stranded model of DNA) with whom he publicly spoke in 2013, quite embarrassing the general public in the person of popular science and simply popular publications. However, for the specialists in Watson's words, there was nothing unexpected - when the general public rushed to the oncologists for comments, they shrugged their shoulders: they say, we have long been aware of the ambiguity of antioxidant drugs. One example: in 1994, as a result of a large-scale study in which more than 29,000 male smokers participated, it turned out that cancer occurred more often in those who took antioxidant beta-carotene pills. In general, the benefits of antioxidants were repeatedly tried in clinical trials and in animal experiments, but the results were often not as expected. In the same 2013, an article appeared in The Journal of the American Medical Association , stating that vitamin E, beta-carotene and large doses of vitamin A can increase your chances of premature death, regardless of whether you are healthy or sick. Someone with a chronic disease.

Such works gradually accumulated decently, but they all consisted of the results of medical and statistical analysis, which said nothing about the mechanisms of the negative effect of antioxidants. However, molecular “mechanistic” work did not take long to come: in 2014, researchers from the University of Gothenburg reported on the pages of Science Translational Medicine that antioxidants, reducing the level of oxygen radicals, thereby turning off the p53 protein, whose task is to monitor the level of mutations in the cell. If a cell is threatened with degeneration into a malignant one, p53 triggers apoptosis, a program of cellular self-destruction. Last year, the same authors made another publication concerning melanoma - this tumor is already known for its tendency to metastasize, and antioxidants, as it turned out, also intensify the appearance of melanoma metastases.

In the new article that appeared recently in Science Translational Medicine , we are already talking about several types of tumors at once. Hongting Zheng and his colleagues at the Third Military Medical University in Chongqing analyzed the effect on cancer cells of several antidiabetic drugs, including some insulin analogues and the well-known metformin. The common feature of these drugs was that they contained type 4 dipeptidyl peptidase inhibitors (IDPP-4) and alpha lipoic acid inhibitors. Both dipeptidyl peptidase inhibitors and alpha lipoic acid reduce blood sugar and help to overcome insulin resistance of the tissues (the main symptom of type 2 diabetes).

It turned out that antidiabetic drugs stimulated the migration and invasion of new tissues of metastatic cells originating from melanoma and from tumors of the lung, intestines, breast, liver and ovaries. As the authors of the work emphasize, cell division did not accelerate, that is, drugs only accelerated the spread of cancer, but not its growth (which, however, is not easier). Most of the experiments were performed in vitro, in cell culture, and not with a real tumor in a living organism, however, in the case of liver cancer and colon cancer, they were transplanted into mice, after which they observed how the tumor cells actively dispersed through healthy tissues.

But where does antioxidants come from? First, alpha-lipoic acid itself is an antioxidant, and secondly, further experiments have shown that dipeptidyl peptidase inhibitors also reduce the level of oxidative stress in cancer cells. And, importantly, it was the antioxidant effect of drugs that was associated with metastasis: if the tumor cells specifically intensified oxidative stress, then they ceased to actively migrate from the primary tumor, despite the presence of antidiabetic substances with antioxidant properties.

The researchers tried to dig even deeper, and eventually came to the transcription factor called NRF2. Transcription factors refer to special proteins that bind to specific sequences in DNA, enhancing or weakening transcription — the synthesis of an RNA copy on a desired gene. It is through transcription factors that the lion’s share of regulatory signals governing genetic activity passes. It turned out that all the dipeptidyl peptidase inhibitors taken for the experiment activated the NRF2 factor, and it was his activation that caused the cancer cells to settle - when NRF2 was artificially turned off, the tumor metastasizing activity fell, and less proteins needed for traveling appeared in its cells. That is, the result is the following scheme: dipeptidyl peptidase inhibitors contained in medicines against diabetes, due to their antioxidant effect, act on the transcription factor NRF2, and it, in turn, “awakens” metastatic genes. Another drug component, alpha lipoic acid, according to the researchers, works the same way.

It is curious that about NRF2 it was known that its activity increases under the action of oncogenic proteins, and that cancer cells need it to extinguish oxidative stress — that is, NRF2 apparently activates not only “migration” genes, but also antioxidant.

It must be emphasized here that such drugs that stimulate metastatic processes do not cause cancer. And here you can recall the work of researchers from McGill University, who published an article in Cancer Prevention Research in 2012, in which they said that antidiabetic metformin prevents the occurrence of tumors - and it prevents them because it reduces oxidative stress. That is, while there is no cancer, the antioxidant makes it so that it does not continue anymore, but as soon as the cancer cell appears, the effect changes to the opposite.

Anyway, if you consider that diabetes and malignant tumors often accompany each other, there is a problem how to choose the right therapy. Here, of course, we need additional studies, including clinical ones, which would assess how harmful the effects of all the above-mentioned drugs depend on the dose - maybe there is no problem, if it turns out that the antidiabetic properties of drugs appear at lower doses. than the ability to push the tumor to metastasis.