Antioxidants Cancer Can Metastasize
Breast Cancer Cell (Photo by Visuals Unlimited / Corbis.)
Diabetes medications that reduce oxidative stress cause cancer tumors to metastasize.
It is known that oxygen radicals - the so-called special molecules, which include oxygen and which are characterized by a very high oxidative activity due to an unpaired electron - can greatly damage DNA.
When there are many 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 oxidizing agents are obtained as a by-product of some important cellular processes, so that in the course of evolution living beings have developed tools for their neutralization.
Lung cancer cells in the lymph node. (Photo by NCI / PHANIE / phanie / Phanie Sarl / Corbis.)
However, the built-in antioxidant defense systems may not 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 cancer spoils DNA heavily, no matter how malignant a tumor is, it will die anyway - in fact, the mass of anti-cancer drugs does exactly that, which makes mutations in the DNA of tumor cells. Then it turns out that antioxidants play into the hand of cancer, saving its genes from damage. This logic was in the arguments of James Watson (recall - one of the legendary authors of the double-stranded model of DNA), with whom he publicly spoke in 2013, very confusing the general public in the face of popular science and simply popular publications. However, for specialists, Watson’s words were not unexpected - when the general public rushed to the oncologists for comments, they shrugged: they say that 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 was found that cancer was more likely to occur in those taking antioxidant beta-carotene tablets. In general, the benefits of antioxidants have been tried repeatedly in clinical trials and in animal experiments, but the results often did not turn out as expected. Also in 2013, the Journal of the American Medical Association published an article stating that vitamin E, beta-carotene, and large doses of vitamin A can increase your chances of premature death, whether you are healthy or sick. Something chronic disease.
Similar works gradually accumulated decently, but all of them were the results of a medical-statistical analysis, which did not say anything about the mechanisms of the negative effect of antioxidants. However, 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 lowering the level of oxygen radicals, thereby turn off the p53 protein, whose task is to monitor the level of mutations in the cell. In case the cell is threatened with malignant transformation, p53 triggers apoptosis, a program of cellular self-destruction. Last year, the same authors made another publication regarding 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 recently published in Science Translational Medicine , we are already talking about several types of tumors. Hongting Zheng and colleagues at the Third Military Medical University in Chongqing analyzed the effects of several antidiabetic drugs on cancer cells, including some insulin analogues and the famous metformin. Common to these drugs was that they contained type 4 dipeptidyl peptidase enzyme inhibitors (IDPP-4) and alpha lipoic acid. Both dipeptidyl peptidase inhibitors and alpha lipoic acid lower 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 of new tissues of metastasis cells originating from melanoma and from tumors of the lungs, intestines, mammary gland, liver and ovaries. As the authors emphasize, cell division did not accelerate, that is, drugs accelerated only the spread of cancer, but not its growth (which, however, is not easier). Most of the experiments were performed in vitro, in a 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 tumor cells actively scattered through healthy tissues under the influence of antidiabetic drugs.
But where does the antioxidants come in? 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 precisely the antioxidant effect of the drugs that was associated with metastasis: if the tumor cells specifically increased oxidative stress, then they stopped actively migrating from the primary tumor, despite the presence of antidiabetic substances with antioxidant properties.
Researchers tried to dig even deeper, and eventually came up with a transcription factor called NRF2. Transcription factors are called special proteins that bind to certain sequences in DNA, enhancing or weakening transcription - the synthesis of an RNA copy on the 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 its activation that caused the cancer cells to settle - when NRF2 was artificially turned off, the metastatic activity of the tumor decreased, and fewer proteins needed for travel appeared in its cells. That is, the result is such a scheme: dipeptidyl peptidase inhibitors contained in drugs for diabetes, due to their antioxidant effect, act on the transcription factor NRF2, and it, in turn, “wakes up” metastatic genes. Another drug component, alpha lipoic acid, the researchers say, works the same way.
It is curious that about NRF2 it was known that its activity increases under the influence of oncogenic proteins, and that cancer cells need it to absorb oxidative stress - that is, obviously, NRF2 activates not only “migratory” 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 onset of tumors - and it prevents them because it reduces oxidative stress. That is, while there is no cancer, the antioxidant makes sure that it does not continue to exist, but as soon as the cancer cell appears, the effect reverses.
One way or another, given that diabetes and malignant tumors often accompany each other, the problem arises of how to choose the right therapy. Here, of course, additional studies are needed, including clinical ones, which would evaluate how much the harmful effect of all the drugs mentioned depends on the dose - maybe there is no problem if it turns out that the antidiabetic properties of the drugs appear at lower doses than the ability to push the tumor towards metastases.