A new way to talk about antioxidants

Jacob Schor, ND

October 2007

When Alexander Bell invented the telephone in 1885 he created an enormous problem.  America was still segregated by social classes.  One did not talk to one’s betters, and there was no correct greeting to use in addressing an unknown person, potentially of a different class.  Ringing phones were better left unanswered.  Bell proposed answering the phone by shouting, “Ahoy, Ahoy”, a greeting already used on the high seas to address unknown persons.  Thomas Edison made a proposal of his own, suggesting phones be answered with, “Hello,” a derivation of the term “Halloo” that was already used to call out to a ferry operator across a river.  Edison’s entry obviously has won out.  New situations sometimes call for new vocabulary.

I bring up this story because it is time for us to find some new vocabulary.  It’s time to stop labeling stuff as antioxidants: we need new and more descriptive terms. 

I was taught that an antioxidant is a substance that prevents or slows the breakdown of another substance by oxygen.  Nutrients such as beta-carotene, vitamin C, vitamin E, and selenium are the classic examples. They are supposed to scavenge free radicals, molecules with one or more unpaired electrons. Free radicals rapidly react with other molecules, starting chain reactions in a process called oxidation.  Antioxidants stop this process.  At least that is what Dr. Anna  MacIntosh taught us once upon a time

When it comes to cancer prevention or cancer treatment this antioxidant business gets interesting.  Many of the things that trigger cancer do so by causing oxidative damage to healthy cells, hence the idea that antioxidants are protective against cancer.  Many of the things that kill cancer cells do so by causing oxidative damage and so we struggle with the straight medical world’s theory that antioxidants interfere with cancer treatment. 

Forget the term antioxidant.  What we really care about are two closely related things:  chemicals which stimulate the generation of Reactive Oxygen Species (ROS), and the chemicals, such as glutathione, which quench Reactive Oxygen Species.  High levels of ROS in an otherwise healthy body cause damage and are a risk factor for disease.  We usually want to keep their levels under control and cells accomplish this with glutathione.  Yet in a body diseased with cancer, ROS are the main weapon to destroy cancer cells. In the medical world chemo and radiation therapy are used to raise ROS.  The point here is that sometimes we want to lower levels of ROS and sometimes we want to increase them.  Sometimes we want more glutathione and sometimes we want to get less of it.

This reminds me of a story about Bob Dole.  Back when he was campaigning for the presidency he appeared along with Bill Clinton for an interview.  The interviewer asked Clinton what kind of underwear he wore, “boxers or briefs?”  “Boxers.” Replied Clinton looking rather smug.  The interviewer turned to Bob Dole and asked the same question.

“Depends” responded Dole.

The things we call antioxidants don’t always do what we ‘want’ them to; with antioxidants, it depends.  Many of the classic antioxidant vitamins can do the opposite and actually stimulate the production of ROS in cancer cells.

In some studies antioxidants work like one would expect:, they decrease Reactive Oxygen Species, especially vitamin C, protecting cancer cells from death caused by treatment.   But this is not always what happens.   It depends.

A recent study suggests high dose intravenous vitamin C kills cancer cells because it is converted into hydrogen peroxide, a potent free radical that kills cells. (Science News October 15, 2005 vol. 168 page 253)

Vitamin C increases differentiation in hepatoma cells by increasing hydrogen peroxide.   What is vitamin C, our poster child of antioxidants, doing increasing hydrogen peroxide?


Selenium is another example.  Selenium is always on that list of antioxidants we rattle off, you know, “Vitamins A, C, E, zinc and selenium.”  Yet in cancer cells, selenium stimulates apoptosis by generating Reactive Oxygen Species.   So does vitamin D.

 

The hormone melatonin is also typically described as an antioxidant, yet it too kills cancer cells by generating Reactive Oxygen Species.   Curcumin too; it induces apoptosis by generating reactive Oxygen Species.   The story is similar with berberine in leukemia.   The parthenolides found in feverfew also destroy cancer cells via ROS.  

(If you aren’t confused about antioxidants at this point then you haven’t been paying attention)

There’s another side to this equation.  N-acetyl-cysteine (NAC) can stop this cancer destroying process. It stops vitamin K-3, vitamin C, fever few and probably other things we once called antioxidants from killing cancer cells. NAC increases glutathione levels. What about glutathione? Let me side track a moment.

For years many of us encouraged cancer patients to increase their glutathione levels. Supplementation with NAC, straight glutathione or glutathione in that patented combination with anthrocyanins, was supposed to protect one’s healthy cells while targeting cancer cells.  It’s time to forget those ideas.  Glutathione stops ROS generating therapies from killing cancer cells.  It stops the parthenolides from killing cancer cells.   It stops Vitamin K-3 from killing cancer cells.  Vitamin K-3, by the way, especially in combination with vitamin C, has a bizarre effect on cancer cells, causing a unique form of cell death called Autoschizis.   Rather than dying via apoptosis, the K-3 and C combination convinces cancer cell to slash itself (self cutting), allowing the cell cytoplasm to bleed out. In contrast to this cellular Hari-kari, apoptosis looks rather tame. The mechanism for vitamin K-3’s action appears to be generation of hydrogen peroxide.   At this point I discourage supplements that increase glutathione during cancer treatment.  Glutathione shuts off autoschizis.

These days glutathione depletion in itself can be seen as a cancer treatment strategy or as one to be used along with stuff which increases ROS.  Glutathione depletion triggers apoptosis in prostate cancer cells.    Research suggests that depleting glutathione may increase the chemotherapy tumor kill in pancreatic,    melanoma, and colon cancer   The herb Salvia, it turns out, stimulates apoptosis in cancer cells via glutathione depletion.    NAC, by the way, also stops Salvia from killing cancer cells.   Typically, say after surgery, we think of l-glutamine as being protective by maintaining glutathione, but in cancer cells, it may do the opposite. In a recent study, a diet high in l-glutamine decreased glutathione and as a result was useful in killing cancer cells.  

Forget the term antioxidant.  It leads to generalizations that all too often aren’t true and don’t work. What these chemicals actually do inside a cell depends on the situation.  Sometimes they quench free radicals like we were taught, sometimes, and it seems to be especially in cancer cells, they do the opposite and generate Reactive Oxygen Species.  If vitamin C can raise hydrogen peroxide levels how can you call it an antioxidant?  This isn’t something easily explained either to a patient or the patient’s oncologist.  Let’s just forget the term antioxidant. It only causes confusion, misunderstanding and misplaced worries.  It’s time for some new language.

Instead let’s think and talk in terms of what this stuff actually does.  What does it do in a healthy cell or in a diseased cell?  Does it generate or induce the production of Reactive Oxygen Species?  If yes, call it a ROS Inducer.  If it lowers the amount of Reactive Oxygen Species then call it a ROS Quencher.  Let’s do the same for glutathione.  Call it either a Glutathione Inducer or Glutathione Depleter.  These are the things we need to track these days.  So let’s use terms that are descriptive.  Calling something an antioxidant doesn’t tell us what it does in the cell anymore. It doesn’t tell us what we really need to know. 

References: 

Mantovani G: Reactive oxygen species, antioxidant mechanisms, and serum cytokine levels in cancer patients: impact of an antioxidant treatment. J Environ Pathol Toxicol Oncol. 2003;22(1):17-28.

Frank J et al: Ascorbic acid suppresses cell death in rat DS-sarcoma cancer cells induced by 5-aminolevulinic acid-based photodynamic therapy.  Free Radic Biol Med. 2006 Mar 1;40(5):827-36. Epub 2005 Nov 2.

  Zheng QS et al: Ascorbic acid induces redifferentiation and growth inhibition in human hepatoma cells by increasing endogenous hydrogen peroxide. Pharmazie. 2002 Nov;57(11):753-7.

Zhao R et al: Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells.  Cancer Res. 2006 Feb 15;66(4):2296-304.

Ravid A and Koren R: The role of reactive oxygen species in the anticancer activity of vitamin D. Recent Results Cancer Res. 2003;164:357-67.

Buyukavci M et al: Melatonin cytotoxicity in human leukemia cells: relation with its pro-oxidant effect. Fundam Clin Pharmacol. 2006 Feb;20(1):73-9.

Medina-Navarro R et al:  Pro-oxidating properties of melatonin in the in vitro interaction with the singlet oxygen.  Endocr Res. 1999 Aug-Nov;25(3-4):263-80.

Moussavi M et al:  Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis. 2006 Feb 25; [Epub ahead of print]

Lin CC et al:  Apoptosis of human leukemia HL-60 cells and murine leukemia WEHI-3 cells induced by berberine through the activation of caspase-3.  Anticancer Res. 2006 Jan-Feb;26(1A):227-42.

Guzman ML et al:  The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.  Blood. 2005 Jun 1;105(11):4163-9. Epub 2005 Feb 1.

Zhang S et al:  Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 2004 May 28;208(2):143-53.

Lin C et al:  Vitamin K3 triggers human leukemia cell death through hydrogen peroxide generation and histone hyperacetylation. Pharmazie. 2005 Oct;60(10):765-71.

Coffey RN et al:   Thiol-mediated apoptosis in prostate carcinoma cells. Cancer 2000 May 1;88(9):2092-104

Schnelldorfer T  et al: Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells. Cancer 2000 Oct 1:89(7):1440-7

    Pendyala L et al:  Effect of glutathione depletion on the cytotoxicity of cisplatin and iproplatin in a human melanoma cell line. Cancer Chemother Pharmacol 1997;40(1):38-44

Moussavi M et al:  Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis. 2006 Feb 25; [Epub ahead of print]

Liu J et al: Role of intracellular thiol depletion, mitochondrial dysfunction and reactive oxygen species in Salvia miltiorrhiza-induced apoptosis in human hepatoma HepG2 cells.  Life Sci 2001 Sep 7;69(16):1833-50

Benlloch M et al:  Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. J Biol Chem. 2006 Jan 6;281(1):69-79. Epub 2005 Nov 1.


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