Is Vitamin C an Antioxidant or a Pro-oxidant

 

How can vitamin C be both an antioxidant and a pro-oxidant?  This is a question and yet a true statement at the same time that confounds many doctors treating cancer today.  As I stated in a previous post, the environment as well as the dose dictates the responseRecent research highlights this dual effect [1] [2].

 

Vitamin C, especially at the higher dosages, which can only be obtained through IV vitamin C delivery, has been shown to be a potent pro-oxidant (not an antioxidant) in cancer cells. In part  because of the dose, but also because of the unique environment in the tumor microenvironment and cancer cells.   The base-line level of ROS in the cancer cell is already elevated because of the compromised detoxification capacity of the cancer cell. Cancer’s accelerated growth and high metabolic requirement appears to be the primary cause of this increase in base-line ROS.  It is the pro-oxidant activity of vitamin C in cancer cells that generates additional increase in the levels of ROS, such as H2O2, OH−, ·O2−, that then can, in part, overwhelm the cancer cell’s detoxification capacity that ultimately results in its destruction. This occur’s in cancer cells as a result of their compromised and depleted detoxification enzymes (catalase, superoxide dismutase, glutathione peroxidase).

 

Hydrogen peroxide (H2O2) works more like a secondary messenger that ends in oxidation with the free radicals OH− and ·O2−, rather then the end cause of oxidation. New research points to H2O2 as the ultimate end-product of vitamin C [3] [4]. Though H2O2 is a pro-oxidant, it has a significantly longer half-life and a greater reach in effect due its increase in diffusion distance [5]. It has been shown that the vitamin C cancer cell death inducing mechanism is dependent on hydrogen peroxide (H2O2) formation with ascorbate radical as an intermediate [6].

 

Just as in rust, cancer requires metal to interact with the oxygen for oxidation to occur. In cancer, I give you iron (Fe) and stored iron (Ferritin). Iron is the redox-active metal that catalyzes the production of ROS through the Fenton and Haber–Weiss reactions. The result is the formation of highly damaging hydroxyl free radicals. In the presence of this high ROS onslaught, cancer cells carry a high labile iron pool due to an increase in iron transport into the cancer cell and a decrease in the transport of iron out of the cancer cell.

 

In the presence of the high ROS and metals (iron, copper…) present in cancer, the oxidative process is set. The therapeutic vitamin C dose, again only achievable by the IV route, is converted to the oxidative H2O2 messenger outside the cancer cell, in the tumor microenvironment, and then diffuses or is transported inside the cancer cell to then interact with the high labile iron pool to create overwhelming oxidative stress, deplete the glutathione pool in the cancer cell, deplete nicotinamide adenine dinucleotide (NAD), to cause oxidative damage— again, think cellular rust. The end result is an oxidative stress crisis, energy crisis, and detoxification crisis in cancer cells. This intra-cellular process of oxidative stress and oxidative damage begins the death spiral within the cancer cell which triggers cell death (apoptosis, ferroptosis…).  In addition, Reactive Nitrogen Species (RNS) via Nitric Oxide (NO), can also play a part in the pro-oxidative process as well.  Where there is iron, or other redox-active metals, whether on the body of the car or in the cell of the body, oxygen will interact with it to create rust, oxidative stress and potentially oxidative damage.

 

Another key factor that separates cancer cells from healthy cells is that cancer cells lack the appropriate levels of certain detoxification enzymes, such as catalase, superoxide dismutase (SOD), and glutathione perioxidase. These detoxification enzymes counter high ROS levels through the reduction of oxidative stress and decrease the oxidative damage potential.  This appears to be more true in cancer cells that lack stem activity compared to cancer stem cells.  We will discuss this at a later post: the difference in ROS in cancer cancer cells without stem activity versus cancer cells with stem activity.  Healthy cells, that is non-cancer cells, retain appropriate catalase, SOD, and glutathione perioxidase activity and are thus perfectly capable of reducing the high ROS levels, prevent oxidative stress and the associated potential oxidative damage. Vitamin C, thus, functions as an anti-oxidant in healthy cells, but as a pro-oxidant in cancer cells, all dictated by the environment. The same pro-oxidative dose of vitamin C yields different effects dictated by different environments.

 

The story for vitamin C does not end there.  Vitamin C also behaves as an inhibitor of the glycolysis pathway (see image below), decoupler of the Pentose Phosphate Pathway (PPP), decoupler of oxidative phosphorylation, depletes NAD, glutathione (GSH), and depolarizes cancer cell membrane polarization.  Wow!!! One would think this was some new pharmaceutical wonder-drug, but it is just the power of vitamin C.

 

Glycolysis is a key pathway in the cell cycle of energy production and the

primary mechanism of energy production in cancer cells. This was first described by Otto Warburg in the early 20th century. His suggestion that cancer cells paradoxically preferentially use up to 10 fold more glucose and produce more lactic acid byproduct in aerobic conditions is called that Warburg effect that appropriately bears the authors name [7]. Vitamin C targets and blocks the activity of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis.  This blockade of the GAPDH enzyme shuts down a cancer cells favorite way to make energy with glucose. The impact of vitamin C, as so many natural therapies do, ripple throughout the entire body. Try to find this similar ripple effect from the conventional medicine one for one monkey wrench approach. But this is a topic for another day.

 

Is vitamin C an antioxidant or a pro-oxidant?  The answer is Yes!  Vitamin C can be a pro-oxidant in the tumor microenvironment of cancer cells and yet can be an anti-oxidant in healthy cells all at the same time in the same body.  Same vitamin C, same dose, different environments in the same body, amazingly yields different effects. Beyond dose, new research points to fact that the environment is equally dictating the effects. This is cutting edge thought found in the recently published science.

 

The pro-oxidative potential of vitamin C dominates in cancer cells in contrast to non-cancer cells.  The environment of these cells are different in every way. Yet, the exist within the same individual with cancer. Today, the malignant tumors are recognized to have their own tumor microenvironment (TME). Heck, they even have their own tumor microbiome. They are different in their environment, different in cell metabolism, different in redox potential, different in detoxification potential, different in antioxidant and pro-oxidant potential…  In fact, you can say the same about cancer cells that lack stem activity in comparison to cancer stem cells, but that is also another topic for another time.

 

So much to write about. So much to discuss. These truly are exciting times in field of integrative medicine, particularly integrative cancer.

 

The functions highlighted above make vitamin C a potent, targeted anti-cancer therapy that leaves healthy cells virtually unharmed. Interestingly enough, this is very similar to the effects of hyperthermia. I wonder what would happen if one combined these therapies in the treatment of cancer? Hmmmm… A therapy that attacks cancer and heals the body at the same time—what a great combination and a novel concept!  Now you are informed. Be empowered. Inform others.

[1] Kaźmierczak-Barańska J, Boguszewska K, Adamus-Grabicka A, Karwowski BT. Two Faces of Vitamin C-Antioxidative and Pro-Oxidative Agent. Nutrients. 2020 May 21;12(5):1501. doi: 10.3390/nu12051501.

[2] Li W-N, Zhang S-J, Feng J-Q, Jin W-L. Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment. Cancers. 2022; 14(11):2608. https://doi.org/10.3390/cancers14112608

[3] Ngo B, Van Riper JM, Cantley LC, Yun J. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer. 2019;19(5):271-282. doi:10.1038/s41568-019-0135-7

[4] Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, Choyke PL, Pooput C, Kirk KL, Buettner GR, Levine M. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8749-54. doi: 10.1073/pnas.0702854104.

[5] Kramarenko GG, Hummel SG, Martin SM, Buettner GR. Ascorbate Reacts with Singlet Oxygen to Produce Hydrogen Peroxide. Photochemistry and Photobiology. Nov 2006;82(6):1634-1637. https://doi.org/10.1562/2006-01-12-RN-774

[6] Roa FJ, Peña E, Gatica M, Escobar-Acuña K, Saavedra P, Maldonado M, Cuevas ME, Moraga-Cid G, Rivas CI, Muñoz-Montesino C. Therapeutic Use of Vitamin C in Cancer: Physiological Considerations. Front Pharmacol. 2020 Mar 3;11:211. doi: 10.3389/fphar.2020.00211.

[7] Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011 May;11(5):325-37. doi: 10.1038/nrc3038.

About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.

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