Antioxidants help cancer to metastasize

Kirill Stasevich, "Science and Life" based on the materials of The Scientist: Antioxidants Again Linked to Cancer's Spread.

It is known that oxygen radicals – the so-called special molecules that contain oxygen and which are characterized by very high oxidative activity due to an unpaired electron – can greatly harm DNA. When there are a lot of such radicals, oxidative stress occurs, and the cell can either simply 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 in the course of evolution, living beings have tools for their neutralization. However, the built–in antioxidant protection systems may not be able to cope with the problem - and then they can be helped by eating some antioxidant drug.

But cancer cells, since they have already appeared, do not need oxidative stress at all. If a cancer's DNA is badly damaged, no matter how malignant the tumor is, it will still die – in fact, a lot of anti-cancer drugs are doing exactly that, which introduces mutations into the DNA of tumor cells. Then it turns out that antioxidants play into the hands of cancer, saving its genes from damage. This was the logic in the reasoning of James Watson (recall – one of the legendary authors of the double-chiral DNA model), with whom he publicly spoke in 2013, greatly embarrassing the general public in the face of popular science and just popular publications. However, there was nothing unexpected for specialists in Watson's words – when the general public rushed to oncologists for comments, they shrugged their shoulders: they say, we have been aware of the ambiguity of antioxidant drugs for a long time. One example: in 1994, as a result of a large-scale study involving more than 29,000 male smokers, it turned out that cancer was more common in those who took antioxidant beta-carotene tablets. In general, the benefits of antioxidants have been repeatedly tested in clinical studies and in animal experiments, but the results often did not turn out as expected. In the same 2013, an article was published in The Journal of the American Medical Association, which stated 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 have some chronic disease.

There were a lot of similar works gradually accumulated, but all of them were the results of a medical and statistical analysis that said nothing about the mechanisms of the negative effect of antioxidants. However, the molecular "mechanistic" work was not long in coming: in 2014, researchers from the University of Gothenburg reported on the pages of Science Translational Medicine that antioxidants, by reducing the level of oxygen radicals, thereby turn 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 increase the appearance of melanoma metastases.

In a new article (Wang et al., NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis), which appeared recently in Science Translational Medicine, we are already talking about several types of tumors at once. Hongting Zheng and his colleagues from the Third Military Medical University in Chongqing analyzed the effect of several antidiabetic drugs on cancer cells, including some insulin analogues and the most famous metformin. What these drugs had in common was that they contained inhibitors of the enzyme dipeptidyl peptidase type 4 (iDPP-4) and alpha-lipoic acid. Both dipeptidyl peptidase inhibitors and alpha-lipoic acid reduce blood sugar and help overcome tissue immunity to insulin (the main symptom of type 2 diabetes).

It turned out that antidiabetic drugs stimulated the migration and invasion into new tissues of metastatic cells originating from melanoma and from tumors of the lungs, intestines, breast, liver and ovaries. As the authors of the work emphasize, cell division was not accelerated, that is, drugs accelerated only the spread of cancer, but not its growth (which, however, is not easier). Most of the experiments were carried out 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 tumor cells were observed to actively disperse into healthy tissues under the action of antidiabetic drugs.

But what do antioxidants have to do with it? Firstly, 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 oxidative stress was specifically increased in tumor cells, then they stopped actively migrating from the primary tumor, despite the presence of antidiabetic substances with antioxidant properties.

The researchers tried to dig even deeper, and eventually came up with a transcription factor called NRF2. Transcription factors are special proteins that bind to certain sequences in DNA, strengthening or weakening transcription – synthesis of an RNA copy on the desired gene. It is through transcription factors that the lion's share of regulatory signals that control genetic activity passes. It turned out that all the dipeptidyl peptidase inhibitors taken for the experiment activated the NRF2 factor, and it was its activation that prompted cancer cells to settle – when NRF2 was artificially turned off, the metastatic activity of the tumor fell, and fewer proteins needed for travel appeared in its cells. That is, the result is the following scheme: dipeptidyl peptidase inhibitors contained in anti-diabetes drugs, due to their antioxidant effect, act on the transcription factor NRF2, and it, in turn, "wakes up" metastatic genes. Another medicinal component, alpha-lipoic acid, according to the researchers, works in the same way.

Interestingly, it was known about NRF2 that its activity increases under the action of oncogenic proteins, and that cancer cells need it to extinguish oxidative stress – that is, obviously, NRF2 activates not only "migration" genes, but also antioxidant ones.

It should be emphasized here that such drugs that stimulate metastatic processes do not cause cancer. And here we 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 exist further, but as soon as the cancer cell appears, the effect reverses.

Anyway, if we consider that diabetes and malignant tumors often accompany each other, there is a problem of how to choose the right therapy. Here, of course, additional studies are needed, including clinical ones, which would assess how much the harmful effect of all the mentioned drugs depends on the dose – maybe there is no problem here if it turns out that the antidiabetic properties of drugs manifest at lower doses than the ability to push the tumor to metastases.

Portal "Eternal youth" http://vechnayamolodost.ru  15.04.2016