Larry H Bernstein, MD, FACP, Reporter
Hypothesis – following on James Watson
A new hypothesis that focuses on reactive oxygen species (ROS) proposes that antioxidant levels within cancer cells are a problem and are responsible for resistance to treatment.
The theory destroys any reason for taking antioxidative nutritional supplements, because they “more likely cause than prevent cancer,” according to Nobel laureate James Watson, PhD, from Cold Spring Harbor Laboratory, New York.
Dr. Watson, who shared the Nobel prize for unraveling the structure of DNA, regards this theory as being “among my most important work since the double helix,“ notes a press release from his institution, where he has been director since 1968.
The theory was published online January 8 in Open Biology.
Dr. Watson explains that
the vast majority of agents used to directly kill cancer cells, including
- ionizing radiation,
- most chemotherapeutic agents, and
- some targeted therapies,
work by generating — either directly or indirectly — ROS that block key steps in the cell cycle.
This generation of ROS creates a hypoxic environment in which cancers cells undergo a transformation from epithelial to mesenchymal cells (EMT).
These transformed cells almost inevitably possess very high amounts of antioxidants, which effectively block the effects of anticancer treatments, Dr. Watson notes. Once a cancer becomes resistant to chemotherapy, it usually is equally resistant to ionizing radiation, he points out.
In addition, these transformed EMT cancer cells generate free-floating mesenchymal cells, which have the flexibility and movement that allows them to
- metastasize to other body locations (brain, liver, lung).
- “Only when they have moved do most cancers become life-threatening,” Dr. Watson notes.
Interestingly, the widely used antidiabetic drug metformin has been shown to preferentially kill mesenchymal stem cells. “In a still much unappreciated article published 3 years ago,
- ” metformin added to chemotherapy
- “induced prolonged remission if not real cures” in mouse models of cancer
(Cancer Res. 2009;69:7507-7511), Dr. Watson writes.
He notes that clinical trials are currently looking to see if adding
- metformin to chemotherapy provides clinical benefits
- diabetics who have been using metformin regularly have a reduced incidence of many cancers.
Resistance to Therapy From Antioxidants in Cancer Cells
Dr. Watson proposes that anticancer therapies work by generating ROS, which cause apoptosis.
However, as cancer cells evolve, they produce antioxidant proteins that block this effect, such as
- superoxide dismutase,
- catalase, and
The fact that cancer cells largely driven by RAS and Myc are among the most difficult of cancers to treat
- could be due to their high levels of ROS-destroying antioxidants, Dr. Watson argues.
- High antioxidative levels might also explain the effective incurability of pancreatic cancer, he adds.
If this theory is correct, then drugs that lower antioxidant levels within cancer cells would be therapeutic.
In fact, the ROS-generating agent arsenic trioxide has been shown to reduce levels of glutathione and thioredoxin. Arsenic trioxide is
- currently being used to treat promyeloblastic leukemia, but this theory
- suggests that the drug could be useful in many major cancers.
Nutritional Antioxidants Could Be Harmful
One far-reaching implication of this theory is that antioxidants as nutritional supplements, including
- vitamins A, C, and E, and
- selenium, could be harmful in cancer.
For years, such supplements have been widely hyped for cancer prevention and/or treatment, as has
- encouragement to eat colorful fruit and berries, which contain antioxidants.
The time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.
However, Dr. Watson warns that recent data strongly hint that much of the untreatability of late-stage cancer might be the result of “its possession of too many antioxidants, [so]
- the time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.”
Many nutritional intervention trials have shown no obvious effectiveness in preventing gastrointestinal cancer or in lengthening mortality, he writes. “In fact, they seem to slightly shorten the lives of those who take them.”
Hence, he concludes, “blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.”
Very Complex Process
Maurie Markman, MD, national director for medical oncology at the Cancer Treatment Centers of America, who writes the Medscape Markman on Oncology blog, was asked to comment on the theory.
“The importance of the critical relationship between oxidating activity and antioxidants in the normal functioning of cells has been recognized by many investigators, and it is not surprising that this process would be quite relevant in cancer. However,
- it must be emphasized that this is a very complex process and the balance between these powerful influences at the cellular level is certain to be very carefully controlled.
- it should be noted that antioxidants are components of our normal diets.
- it is most unlikely that a simple approach to somehow removing antioxidants from the body will be a useful strategy in cancer management,”
Open Biol. 2013;2:120144. Full text
Comment: Dr. Larry H. Bernstein
Pathology has a tradition going back to Rokitanski and Rudolph Virchow. The complexity of this issue is that there is a concomitant metabolic abnormality. and a series of step-by-step changes in the cell related to a change from aerobic to anaerobic glycolysis in the presence of oxygen, noted by Otto Warburg, which is accompanied by mutations, which combined lead to cellular prolieration and cell migration. When you reach the stage of metastasis to distant sites, the process most likely is irreversible.
The proposal that the epithelial cells become mesenchymal is not tenable in the case of most epithelial tumors, at least in the sense that they are not sarcomas. The problem is that the intercellular adhesion breaks down, and the underlying stroma also is malignant. If that is what is inferred, it is a new twist.
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