When is an antioxidant not an
antioxidant? This curious question was
explored in a scientific poster that Dr. Block presented at the 10th
International Conference of the Society for Integrative Oncology (SIO), held October
20-22 of this year. The answer to the question was suggested in the title of
the poster, “Antioxidants as pro-oxidants in cancer cells.” What, you might ask, is a pro-oxidant? As the name suggests, it’s the opposite of an
antioxidant! Antioxidants neutralize
free radicals, while pro-oxidants stimulate and produce free radicals, or, in
scientific jargon, reactive oxygen species (ROS).
Why are we interested in producing free radicals in cancer cells? Isn’t this the opposite of what we want to do? And why would an antioxidant suddenly turn into a pro-oxidant when you put it into a cancer cell? Actually, it’s well known that many antioxidants can act as pro-oxidants – this fact even appears in Wikipedia! However, the Wikipedia discussion of antioxidants overlooks some new data that are coming to light about pro-oxidants and antioxidants as they relate to cancer treatment.
A possible mechanism has come to light with a new understanding of how chemotherapy agents work. It turns out that the free radicals produced by chemotherapies cause cancer cells to “commit suicide,” a process known as apoptosis. We know that apoptosis is triggered, in part, by free radical damage to parts of the cancer cell. In fact, it’s been suggested that cancer patients avoid antioxidants entirely because of a theoretical fear that they might neutralize this free radical damage and impede apoptosis, both from chemotherapy and from other agents. Dr. Block and his research team, however, realized that this was in direct contradiction to strong data that are very well known among scientists who study natural products. There are, in fact, numerous antioxidants that are well known to actually CAUSE apoptosis in cancer cells. Curcumin, EGCG from green tea, and melatonin are just three of the best-known antioxidants that are widely known to cause apoptosis in a variety of different types of cancer cells. But they don’t cause apoptosis in normal cells, and, in fact, can protect them from many kinds of carcinogenic damage.
So how is it that these well-known antioxidants can be causing apoptosis if they impede free radical activity? Our research team started delving into the literature and found out that there is an explanation for this phenomenon, and also for why it might occur in cancer cells, but not in normal cells. Amazingly, laboratory scientists have discovered ways to tell when a substance causes free radicals to be formed inside of cells. There are substances that are described as molecular probes that test for these intracellular free radicals. And they can easily test any substance to see if it causes apoptosis in either cancer cells or normal cells. What researchers have discovered is that many antioxidants cause apoptosis in cancer cells when they are applied in high doses to cells grown in test tubes. The same doses, however, do not cause apoptosis or otherwise damage normal cells. When the molecular probes are used, scientists find that the high-dose antioxidants cause cancer cells to produce free radicals. This is what may be triggering apoptosis.
Why would this happen in cancer cells and not normal cells? Another line of study has been shedding light on this aspect of the question. It turns out that antioxidants can undergo reactions with metals. Specifically, many of the natural antioxidants that are known to trigger apoptosis in cancer cells have been found to form free radicals when they interact with copper. Cancer cells are well known to have high concentrations of copper and other metals such as iron. Copper in particular plays an important role in the basic metabolic processes of the cancer cells, in angiogenesis as well as in metastasis. Cancer cells need copper for these processes, which are absent in normal cells. When natural antioxidants react with copper, they target cancer cells with free radicals, which can cause apoptosis. This may explain why they cause apoptosis in cancer cells, but not in normal cells.
So when we give antioxidants that generate intracellular free radicals, along with chemotherapy that also creates free radicals, what happens? Do the antioxidants neutralize or interfere with the chemotherapy, or do their pro-oxidant effects dominate? For each of the antioxidants for which our research team found pro-oxidant effects, they also searched for studies in which the antioxidants had been given with chemotherapy drugs. In almost all of these cases, the research indicated that antioxidants actually enhanced the effect of the chemotherapy drugs. These studies were done not only in the test tube, but also in animals that have tumors, and, importantly, in humans. A large review article, for instance, found many experiments in which curcumin was given with chemotherapy (or radiation), increasing its effectiveness. A series of clinical trials conducted in Italy found that high-dose melatonin increased the effects of chemotherapy, but reduced its toxicity to normal tissues. And, while the test-tube studies required high doses of antioxidants to obtain their pro-apoptosis effects, the studies in animals and humans used very reasonable doses.
This very interesting phenomenon may explain why antioxidants did not eradicate the effects of chemotherapy in the randomized trials our research staff reviewed. It certainly deserves more scientific explanation, and Dr. Block and our research team plan to publish a scientific paper on the topic, which will hopefully stimulate more research in this area. Certainly, the researchers at the SIO meeting were very interested in their findings! We hope to report more to you about this interesting topic in the future, since we know that many patients remain confused about the use of antioxidants during cancer treatment.
For more information on The Block Center for Integrative Cancer Treatment, call (847) 230-9107 or visit BlockMD.com.
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