English: Nobel laureate Dr. James D. Watson, Chancellor, Cold Spring Harbor Laboratory. These images are freely available and may be used without special permission. (Photo credit: Wikipedia)
Novel Cancer Hypothesis Suggests Antioxidants Are Harmful
Reporter:
Larry H Bernstein, MD, FCAP
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
- glutathione,
- superoxide dismutase,
- catalase, and
- thioredoxin.
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
- beta-carotene,
- 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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Blackberries are a source of polyphenol antioxidants (Photo credit: Wikipedia)
Reactive oxygen species and detoxifying system (French) (Photo credit: Wikipedia)
English: Major cellular sources of ROS in living cells. Novo and Parola Fibrogenesis & Tissue Repair 2008 1:5 doi:10.1186/1755-1536-1-5 (Photo credit: Wikipedia)
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette