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  • Cancer Investigators Search For Mitochondrial Antioxidants Nature Already Provides

    July 19, 2014: by Bill Sardi

    Researchers at Cold Spring Harbor Laboratory, writing in a recent edition of The New England Journal of Medicine, claim a reason why supplemental antioxidants have failed to consistently reduce the risk for cancer is that they don’t target the precise location where 90% of oxidation takes place – in cellular power plants called mitochondria. [New England Journal Medicine July 10, 2014; Medscape July 11, 2014]

    These researchers are calling for the development of “synthetic” strategies to target the mitochondria and negate the protective effect dietary antioxidants provide cancer cells, ignoring the fact there are many natural antioxidant molecules that already target mitochondria and promote cancer cell death.

    There are a few hundred mitochondria inside every living cell.  Healthy cells increase their production of mitochondrial oxidants (called reactive oxygen species) to stimulate transformation to cancer cells.

    Oxidation can be beneficial.  For example, hydrogen peroxide can be generated in living cells to induce their death which would be advantageous in limiting cancer.  High blood serum concentrations of vitamin C, facilitated by intravenous delivery, transiently produces hydrogen peroxide that selectively kills cancer cells, the precise mechanism these researchers are attempting to develop “synthetically.”  [Science Translational Medicine Feb 5, 2014]

    Investigators note that cancer cells maintain pools of two internally-produced antioxidants called glutathione and thioredoxin.  These protective internal antioxidants allow cancer cells to survive and become immortal rather than die off naturally like other cells in a process called apoptosis (programmed cell death).

    New understanding of antioxidants

    These researchers posit two therapeutic approaches to cancer based upon this “new” understanding of antioxidants.

    First, molecules that prohibit the production of oxidation (reactive oxygen species) in the mitochondria will be more effective at preventing and treating cancer than dietary antioxidants because they ineffectively target the mitochondria.  Mitochondrial antioxidants are known to be more potent cancer inhibitors than the same antioxidants that concentrate in the cytoplasm (watery part) of cells.

    Therefore, the failure of dietary antioxidants in clinical trials might be due to their inability to quell oxidants (rusting agents) at the site of production.

    These researchers also claim it is possible a “synthetic strategy” that disables antioxidants within cancer cells can be developed which would allow hydrogen peroxide to arrest tumor cell growth and promote cancer cell death.  (“Synthetic” means patentable man-made molecules that could make a fortune for their developers.)

    These investigators say the challenge is to identify antioxidants that are selectively used by cancer cells and not healthy cells to promote death of malignant cells or prevent conversion of healthy cells to tumor cells.

    Not new

    While New England Journal of Medicine editors gave top billing to the Cold Spring Harbor Laboratory researcher’s report, this is not a new topic.  For example, over two decades ago researchers at Cornell University wrote about the intentional inhibition of glutathione, a major cellular antioxidant, in order to overcome treatment resistance and kill off cancer cells.  [Pharmacology & Therapeutics 1991]

    The most oft-used glutathione-depleting drug used in lab dish and animal experiments involving cancer is buthionine sulphoximine (BSO).  [Biochemical Pharmacology Oct 1984]  Another glutathione-depleting drug, arsenic trioxide, has also been successfully used to deplete glutathione under experimental conditions. [Proceedings National Academy Sciences July 24, 2007]

    In an attempt to overcome treatment resistance researchers reporting in the Journal of Clinical Oncology in 1994 and Journal Of The National Cancer Institute in 1997 wrote that the use of a glutathione-depleting drug (BSO) was reasonably well tolerated (caused nausea and vomiting) among cancer patients and depleted glutathione to less than 10% of its normal level in white blood cells.  [Journal National Cancer Institute Dec 1997; Journal Clinical Oncology Jan 1994]  But there is no long-term data as to whether this treatment promoted longer patient survival. Glutathione-depleting agents may induce cancer cell death but not prolong cancer patient survival.

    Other molecules that deplete glutathione

    A number of other molecules that deplete antioxidants from cancer cells have been reported.  [Frontiers Bioscience Jan 2006]  For example, a natural molecule, piperlongumine derived from Piper longum L (black pepper spice), induces oxidation and cancer cell death via depletion of glutathione without harming healthy cells. [Nature July 13, 2011]  Other researchers have identified 51 test molecules that inhibit the enzyme that produces glutathione and therefore makes tumor cells more vulnerable to toxic treatments like chemotherapy or radiation treatment.  [Molecular Pharmacology April 7, 2007]

    The main point is that this topic is not new nor unexplored.

    The search for mitochondrial antioxidants

    The search for mitochondrial antioxidants that selectively kill off cancer cells without harming healthy cells shouldn’t be difficult.  Nature already provides quite a few of them.  For example:

    While vitamin E has been slammed as an antioxidant that protects cancer cells and induces tumor cell growth that is not true for all forms of vitamin E. The commercially available alpha tocopherol succinate form of vitamin E targets the mitochondria and stimulates tumor cell death and has been demonstrated to overcome treatment resistance.  [Cellular & Molecular Life Sciences June 2014]

    In 2000 the journal Nutrition & Cancer published a striking report on the ability of allicin, the primary anti-cancer molecule found in fresh-crushed garlic, to selectively kill cancer cells.  Researchers found that allicin depletes glutathione, a major antioxidant produced naturally within cells, resulting in death of tumor cells.  [Nutrition & Cancer 2000]

    Polyphenols, cancer and mitochondria

    Polyphenols, a class of natural molecules derived from spices, herbs, grapes and other botanical sources, are known to target the mitochondria and selectively kill off cancer cells by mechanisms other than glutathione depletion.  [International Journal Cancer April 10, 2002]

    For example, curcumin, the molecule derived from turmeric kitchen spice, induces cancer cell death by a variety of non-toxic mechanisms, particularly in the mitochondria.  [American Association of Pharmaceutical Scientists Journal Sept 11, 2009]

    Resveratrol the mitochondrial powerhouse

    In 1997 cancer researchers, after reviewing thousands of natural molecules for their anti-cancer effects, identified resveratrol (rez-vair-ah-trol), known as a red wine molecule, as an agent that addresses all three stages of cancer — initiation, growth and metastasis (spread).  There is no modern cancer drug that can say that. [Science Jan 10, 1997]

    Since that discovery, noted over a decade ago, resveratrol has been shown to induce DNA damage and thus kill off cancer cells without harming healthy cells. [Clinical Cancer Research Aug 15, 2011]

    Resveratrol has even been shown to target the mitochondria without harming DNA genetic material and induce programmed cell death non-toxically.  Within seconds of resveratrol entering a tumor cell it increases calcium levels and induces tumor cell death.  [Journal Cellular Physiology Feb 2012]  It does this via a mitochondrial mechanism.  [Molecular Pharmacology Dec 2007; Investigative Ophthalmology Sept 2006; Clinical Cancer Research Sept 2007; Antioxidants Redox Signaling Sept 15, 2010; Advances Experimental Medicine Biology 2008; Clinical Cancer Research Sept 2007]

    Resveratrol also inhibits cancer and its spread via other mechanisms, namely by thinning the blood and reduction of inflammation.  [Journal Bioenergetics Biomembranes Feb 2007]

    While polyphenols can be quite toxic when given in high doses and mega-dose resveratrol has been reported to induce kidney failure among patients with a form of bone cancer (multiple myeloma) [British Journal Hematology March 2013; Myeloma Beacon May 6, 2010], a commercially available brand of resveratrol inhibits cancer without inducing toxicity, even at high dose [Experimental Clinical Cardiology Winter 2010] and has not been demonstrated to induce kidney toxicity in animal and human toxicity studies. [Food & Chemical Toxicology Sept 2013]  In particular, Longevinex® activates the Sirtuin3 gene, known as a mitochondrial gene, 295% better than plain resveratrol. [Canadian Journal Physiology Pharmacology Nov 2010]  — ©2014 Bill Sardi,


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