Vitamin C in Leukemia and Lymphoma

Effects of Vitamin C May Depend on Malignancy

Drugs or Orange - what should you take?
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When you think of stress, maybe your mind turns to schedules, deadlines, tests, relationships, or other challenges that a person may face in life. The world today has no shortage of potentially stressful stimuli.

And yet, not every person responds in the same way to these environmental triggers. The sources of individual variation are likely numerous, in part due to our ability to cope and respond adaptively to our environment.

There is a cellular equivalent to stress, as well. Just as we may find our environment particularly stressful at times, the cell’s environment may harbor different types of stressful triggers—for instance, a noxious molecule in the surrounding fluid, or an inability to process the internal cellular molecules properly.

When you think of cancer cells, in particular, you may not immediately associate them with an underlying vulnerability to stress. Cancer cells are often described with terms such as ‘invincible’ and ‘immortal’ in that they seem to reproduce and spread without limits. It turns out, however, that cancer cells operate under a great deal of stress in particular, oxidative stress. And vitamin C may play an important role when it comes to certain enzymes that help cells respond to stress.

What Is Oxidative Stress?

Oxidative stress, in plain terms, is an imbalance in the cellular environment.

As the concept is developed further, this imbalance can be viewed as an uneven battle between production of a harmful foe (free radicals) and the ability of the body to counteract the harmful effects of this foe (via antioxidants).

You may have learned about free radicals in chemistry: officially, they are defined as uncharged molecules that are typically highly reactive and short-lived, with unpaired electrons.

For example, oxygen molecules throughout the body at times split into single atoms of oxygen, each with unpaired electrons.

Electrons want to be in pairs, so these uneven atoms, now called free radicals, seek out other electrons that are part of the body, almost like predators, to pair with an electron that belongs to some other molecule in the body. This is oxidative stress, then, and it causes damage to cells, their membranes, proteins and DNA.

So, why are cancer cells typically operating under a high level of oxidative stress? Well, often these cells have high levels of free radicals at baseline, to begin with, before they even become cancerous. Then, as a cell takes more and more steps toward becoming cancerous, things often change in terms of how that cell runs its own metabolism, potentially resulting in even higher levels of free radicals.

Normally, there is a balance between free radical production and elimination. There are two different “teams,” with one team producing free radicals like superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radicals (OH-), etc., and the other team providing antioxidant defense mechanisms [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), etc.].

When the free radical foe is not well-contained and/or eliminated, the result may be cell damage, with loss of function and integrity of the cell membrane, as well as DNA damage, promoting potentially harmful genetic changes and unregulated cell growth. This latter effect is known as genetic instability, and it can add fuel to the fire as relates to the cell’s malignant journey.

Free radicals and oxidative stress are also associated with a number of human diseases aside from cancer, including heart disease, Alzheimer's disease, Parkinson's disease, and more. There is also a link to aging, with the gradual accumulation of free-radical damage.

Substances that generate free radicals can be found in our environment, including the foods we eat, but they also occur in our bodies as natural products of metabolism.

How Might Substances Like Vitamin C Protect Against Cancer?

Vitamin C has been tried in various studies of the treatment and prevention of cancer; however, results still do not always paint a clear picture. Answers to the question of the role of vitamin C in cancer prevention and treatment may depend on the specific malignancy–and the dose of vitamin C, among other factors.

At low concentrations, vitamin C has an antioxidant role, preventing oxidation. Antioxidant foods, rich in ascorbic acid (vitamin C), carotenoids (vitamin A) and tocopherol (vitamin E), selenium, and flavonoids, are recommended due to their antagonistic action of inhibiting oxidation and free radical production.

However, high levels of vitamin C can increase the production of ATP (generated by mitochondria) inducing programmed cell death in tumor cell experiments, via a pro-oxidant mechanism.

Studies show dose-dependent anti-cancer activity impacting various cellular processes including programmed cell death, the cellular growth cycle, and cell signaling, with increased cancer cell death in lab experiments that treated cancer cells with mitoxantrone (a chemotherapy drug) along with vitamin C.

Will There Be a Role for High-dose Vitamin C in Leukemia?

Thus far, some studies have suggested activity against a wide variety of cancers, but other studies have suggested that vitamin C might make chemotherapy less effective.

The short answer to the above question is “maybe,” and also, “it may depend on the leukemia.” It may be important to look at vitamin C from many different angles before making conclusions about its use in any particular cancer, but some initial findings from laboratory-based studies of hematologic malignancies are encouraging.

A 2017 study on the effect of vitamin C on leukemia cells was published in the journal “Cell.” In their introduction, the authors noted that the evidence for vitamin C as an effective treatment for cancer has remained controversial so far. 

Vitamin C May Impact Enzymes Important in Leukemia

In particular, this group of researchers studied genetic changes in an enzyme called Tet (Ten Eleven Translocation) methylcytosine dioxygenase 2, or TET2. They found interesting interactions with vitamin C and this enzyme—interactions that seemed to improve the efficacy of certain cancer treatments. This was an animal study, so the implications for humans are not yet known, but the results were provocative.

In the body, new blood cells arise from special cells in the bone marrow called hematopoietic stem cells. Prior studies have shown that the TET2 enzyme can make these stem cells grow up into healthy, mature, normal blood cells–cells that end up dying similarly to any other normal cell. In contrast, in leukemia, stem cells do not mature properly, but rather duplicate themselves, multiplying in harmful clones of copycat stem cells.

The effect of such uncontrolled leukemia stem cell growth is to prevent the body from producing enough of the normal, healthy blood cells (eg, neutrophils, lymphocytes) that our immune system needs to fight infection; a reduced supply of new red blood cells can lead to anemia, as well. Thus, a susceptibility to infection and things like weakness or paleness from anemia may oftentimes be among the signs and symptoms of leukemia.

Well, it turns out that in some cases of leukemia, there has been a genetic change, or mutation, that results in a version of the enzyme TET2 that doesn’t work properly. Thus, the 2017 study examined ways in which this enzyme, TET2, might be stimulated to do its job, and notably, whether or not vitamin C can be used in this effort to restore healthy blood cell production.

Vitamin C TET2 Study Results

Researchers genetically engineered mice to inactivate the enzyme TET2, and they found that when TET2 was turned off, the stem cells started to malfunction, and when they turned the gene back on, these malfunctions were reversed.

In leukemia and other blood diseases that may be influenced by genetic changes impacting the TET2 enzyme, only one of the two copies of the TET2 gene is changed. Investigators thus looked at whether vitamin C might be able to make up for the bad, altered, or mutated copy of the gene by boosting the activity of the copy that still functioned normally. They found that with vitamin C, there was a boost to a genetic mechanism that restored TET2 function.

PARP-inhibitors such as olaparib are drugs that are being studied for possible use in different types of blood cancers and leukemia. In this study, researchers combined vitamin C with PARP inhibitors in their animal model to study the interaction. They found the combination worked better, making it even more difficult for the leukemic stem cells to self-renew.

What About Vitamin C in Lymphoma?

As with the findings in leukemia, the research is currently in the pre-clinical stage, meaning that what we know comes from tests of cells and animals in laboratories, but not individuals in clinical trials.

Nonetheless, there are, based on these pre-clinical data, reasons to believe that findings related to TET2 and vitamin C might be applicable to at least some cases of lymphoma.

In lymphoma, TET2 mutations are found most commonly in the T-cell lymphomas. In one lymphoma subtype, angioimmunoblastic T-cell lymphoma, TET2 may be mutated in as many as 76 percent of patients. The TET2 mutation rate is also high in 38 percent of patients with peripheral T-cell lymphoma-not otherwise specified, according to a study by Lemonnier and colleagues, and 13 percent in diffuse large B-cell lymphoma.

A Word From Verywell

While scientists sort out the data regarding vitamin C and its possible role in the prevention and treatment of certain cancers, it is important to be moderate in consuming this vitamin. Too much of a good thing is not necessarily still a good thing. And, it is always best to consult your doctor when initiating any supplementary regimen that could interfere with your treatment.

None of the evidence yet suggests that supplementing with vitamin C on your own, beyond what is recommended, will achieve protective or otherwise beneficial results in leukemia or lymphoma, and such self-experimentation could actually cause harm in certain instances.

In past studies, it has been shown that patients with hematologic malignancies may be deficient in vitamin C. Thus, correcting any existing vitamin C deficiency may be the best place to start.

Sources:

Cimmino L, Dolgalev I, Wang Y, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017 Aug 16. pii: S0092-8674(17)30868-1. doi: 10.1016/j.cell.2017.07.032. [Epub ahead of print].

Lemonnier F, Couronne L, Parrens M, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120: 1466–1469.

Mikirova N, Casciari J, Rogers A, et al. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med. 2012;10:189.

Shenoy N, Bhagat T, Nieves E, et al. Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. Blood Cancer J. 2017;7(7):e587-. doi:10.1038/bcj.2017.65.

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