Article Summary:

Reactive oxygen species (ROS) are molecules that can damage cells and even cause cancers. They are produced inside cells as well as from external sources. ROS do have beneficial, physiologic purposes and are held in check by enzymatic production to rid excess. However, one could argue that humans are exposed to an increasing amount of toxins producing more and more free radicals which cells may not be able to expel. This can lead to ill health, disease and cancer. However, once a cell is in a state of rapid replication, i.e. cancer, these cells produce a greater quantity of ROS and lack the ability to balance intracellular free radicals leaving them in a state nearer the threshold of self destruction. Therapy may be considered to help “push” the cancer cells “over the edge” by added further oxidizing agents or specific nutrients that may increase ROS in cancer cells, causing cell death. We explore four of these nutrients that have shown to do so in this article: Melatonin, Vitamin C, a specific form of Vitamin E, and Selenium.

Everything in Balance

Most everything in human physiology is about balance. Pro-inflammation versus anti-inflammation, for example, demonstrates the necessary tug-of-war that must take place to maintain health. Oxidation versus anti-oxidation is similar. Oxidative stress, a term given by excess oxidation,  may be described as an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. Superoxide radicals (O2•−), hydrogen peroxide (H2O2), hydroxyl radicals (•OH), and singlet oxygen (1O2) are most commonly defined as reactive oxygen species (ROS). But, while considered to be “bad guys” when in excess, they are created in the cells as metabolic by-products and DO have a healthy purpose when in balance. However, should ROS production increase, they start showing harmful effects on important cellular structures, their function, and even be responsible for cancer. (1)

ROS are a subset of what are called “free radicals”. Remember, free radicals are not always “bad” as they serve important functions when kept in balance, termed homeostasis. Although, it is important that we understand “balance” to mean a balance over time. Acute infection, for example, will yield elevated ROS for the purpose to aide elimination of said pathogen, followed by reduction of ROS through enzymatic production of balancers.

ROS Production and Reduction

ROS are produced both inside the cell as well as outside the cell (endogenous and exogenous sources). Endogenously, the mitochondria are responsible for the greatest production and are kept in balance by enzymatic components, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Immune cell activation, inflammation, ischemia, infection, cancer, excessive exercise, mental stress, and aging are all responsible for endogenous ROS production. Exogenous free radical production can occur as a result from exposure to environmental pollutants, heavy metals (Cd, Hg, Pb, Fe, and As), certain drugs, chemical solvents, cigarette smoke, alcohol, and radiation. When these exogenous compounds penetrate the body, they are degraded or metabolized, and free radicals are generated as by-products. (2-7)

Cancer cells are generally thought to have increased levels of ROS, e.g. superoxide and hydrogen peroxide, compared to their normal cell counterparts [8–12]. Increased levels of ROS significantly contribute to: genomic instability, inability to perform differentiated function,
immortalization, uncontrolled cellular proliferation, and the progression to the malignant state [13-15]. The altered metabolism of tumor cells was first reported by Otto Warburg in 1927 [16].

The Warburg effect describes the increased glucose uptake of tumor tissue relative to adjacent normal tissues. This increased glucose uptake may be utilized in the pentose phosphate pathway (PPP) to generate reducing equivalents (i.e., NADPH). Transketolase (TKT) is an enzyme in the PPP and is a critical mediator necessary for regenerating NADPH. Recently, TKT has been shown to be critical in regulating cancer cell metabolism in hepatocellular carcinoma cells [17]. In this model system, TKT inhibition led to increased oxidative distress within a cell. While TKT participates in maintaining ribose 5-phosphate levels, it is therefore necessary for maintaining cell growth – elevated levels seems to equate to more cell proliferation while inhibition results in greater ROS production and inhibition of proliferation. (18)

To simplify the hypothesis as it relates to cancer: While free radicals, including ROS may be a responsible party in damaging a cell and causing rapid replication, i.e. cancer, they are also found, in excess, within a cancer cell. While there is still question as to whether cancer cells produce excess ROS, fail to produce adequate enzymes to rid them, or a combination of both, remains to be explored, one may attempt to exploit this information to both understand mechanisms to aide in killing cancer cells and help explain why previous methods may work.

Therefore, cancer cells, by having excess ROS, are nearer their “lethal dose threshold” than are healthy cells. Chemotherapy, an oxidative agent, utilizes this fact to help “tip over” a cancer cell causing its death. While it may also raise ROS in healthy cells, cell destruction of these occurs less frequently since they are functioning in a more balanced experience as far as ROS production/reduction. New research suggests that natural agents, dose dependently, may also increase ROS in cancer cells making them a novel approach to cancer cell destruction. We’ll explore four of these nutrients next, but first let’s discuss a bit more on BALANCE:

Understanding BALANCE

Under different tissue concentrations, natural chemicals/nutrients may have contradictory, physiological functions. For instance, certain plant polyphenols can function as anti-oxidants in “normal, lower concentrations” and pro-oxidants in higher concentrations. While phytochemicals in diets rich in fruits and vegetables are generally recognized as potent antioxidants with many potential health benefits, excess consumption of the same nutrients can stimulate the biosynthesis of antioxidant enzymes and suppress processes leading to the production of ROS. This paradoxical, dose-dependent function of nutrients may explain why hyper-dosing on nutrients often produces unfavorable responses and even may explain why fad diets may produce an imbalanced physiology.


Melatonin, a hormone held in and released by the pineal gland, is well known for its role in regulating circadian rhythms and helps us fall asleep. It has been suggested to be a compound capable of preventing and treating several cancer types. It can help in regulation of pro-survival signaling and tumor metabolism, the inhibition of angiogenesis and metastasis, and the induction of epigenetic alterations in oncogenes and tumor suppressor genes. It can help with co-morbidities associated with cancer therapies by reducing normal tissue injury associated with radiation and chemotherapy, as well as enhancing the efficacy of chemotherapy, thereby improving cancer survival rates. (19, 20)

At normal physiological doses, Melatonin has shown to scavenge ROS and reactive nitrogen species, functions as an antioxidant as well as anti-inflammatory agent. Melatonin has been shown to enhance the expression of the antioxidant enzymes catalase, superoxide dismutase, and glutathione reductase. It has been shown to mitigate estradiol-induced, oxidative DNA damage, iron-catalyzed lipid peroxidation, along with decreasing copper-mediated DNA damage, giving it strong, anti-cancer properties. It has been also shown to function as a heavy-metal chelator.

These cancer preventative functions of Melatonin may be one piece to help answer questions to the rise in cancer rates. The constant presence of light all hours of the day when the absence of sunlight was to signal sleep and Melatonin release may account for diminished Melatonin blood levels and cessation of its cancer preventative benefits. Furthermore, reduced secretion of melatonin may lead to an increase in reproductive hormone, including estradiol. Increased levels of estradiol are associated with an elevated risk of breast cancer development.

The paradoxical function of Melatonin in someone diagnosed with Cancer

While I could continue to cite research on anticancer effects of melatonin due to its antioxidant function, there is now suggestion that it may function as a pro-oxidant in cancer cells, particularly at higher dosages. The pro-oxidant nature of high-dose melatonin has been shown to promote apoptosis via caspase activation and was shown to be counteracted by N-acetyl-L-cysteine, Trolox, PEG-catalase, and glutathione. (26, 27)  This makes one think that it may not be wise to recommend such antioxidants. It appears that Melatonin selectively disrupts mitochondrial and metal ion metabolism. In human leukemia Jurkat cells, high concentrations of melatonin led to Fas–induced apoptosis via ROS generation, thereby overwhelming already overloaded (with ROS) cancer cells. (22, 23)

In addition to its potential for enhancing cancer therapy, melatonin may also protect normal tissues from cancer therapy–associated toxicity by assuming a role as a donor antioxidant at higher doses. Melatonin has also demonstrated significant activity as a radioprotector, protecting against radiation-induced DNA damage. (24, 25) One study revealed that the combination of melatonin and vitamin C reducedDNA damage in peripheral blood samples. (28)

What is considered “higher dose” for melatonin? While typical recommended dosages for help with sleep range from 2-6mg before bed, therapeutic higher dose melatonin to aide in cancer destruction as well as chemo-protective and radio-protective should consider ranges from 20-100 mg dosed throughout the day. Di Bella has reported that supraphysiological doses delivered intravenously up to a maximum dose of 1 g have limited side effects. (29) It is important to note that all nutrients, taken either orally or intravenously, have a half-life and the half-life of melatonin is approximately 45 minutes.

Vitamin E

There are several natural forms of vitamin E, namely, α-,β-,γ-,δ –tocopherol (TOH) and tocotrienol (TE-OH). In nature, the four inner components of vitamin E, the tocotrienols are surrounded by the four tocopherol rings. Many synthetic forms of vitamin E simply contain the inexpensively synthesized outer rings, still legally vitamin E, but lacking the whole nutrient. Because vitamin E is a more complex molecule, many past studies on its effects on various health conditions have been flawed. When a study was conducted using only the tocopherol rings, it often failed to help as expected. This made sense to naturally minded clinicians but was used to discredit natural methods of care More recent studies conducted have discovered that when the tocotrienols (the four inner components) are used, results can be astonishing.

Vitamin E has also been suggested to have both antioxidant effects in normal tissues as well as pro-oxidant effects in cancer cells. (30) Tocotrienols have been shown to accumulate selectively in cancer cells relative to normal cells following oral administration. They  have been shown to be effective in inducing growth arrest, apoptosis, autophagy, and endoplasmic reticulum stress in cancer cells. (31, 32)

A dosage of 300mg, 1-3 times per day of tocotrienol included form of vitamin E may be a good choice of adjunctive care.


Selenium is another nutrient that tends to be pro-oxidative at higher doses. The associated increase in formation of ROS may tip the redox status of cancer cells, killing the cells. Cells in healthy tissues can cope with these fluxes of oxidative stress, while cancer cells are at the limit of their ability to control the oxidative distress. Generally, organic selenium compounds like selenomethionine, are less toxic at higher concentrations. Because these compounds are not redox active, they do not generate ROS readily so studies have shown that use of the inorganic counterparts like sodium selenite seem to prove better anti-cancer results. (33) Selenium can also be used as an adjuvant for chemotherapy and radiation therapy, acting as a cell protectant to healthy cells.

Preclinical trials on use of higher dose selenium have shown a down-regulation of hypoxia induced factor 1α and 2α (HIFs) and downstream vascular endothelial growth factor (VEGF) and associated oncogenic miRNA 155 and 210, which results in reduced vascular permeability and improved drug delivery into the tumor upon treatment. (34-40)

Dosing selenium depends on its source. Organic sources such as selenomethionine would need up to 4mg, twice per day, a hefty dose by anyone’s standards since most on the market are 200mcg capsules. A better source might be sodium selenite as it is far less expensive and simpler to dose at a mere 100-300 mcg per day.

Vitamin C

Vitamin C has long been heralded as a natural cancer killer but has been horribly maligned but mainstream medicine. Many have argued that its benefits in cancer therapy were from its strong antioxidant effects as vitamin C has been clearly shown to possess these features. However, in nature, doses of vitamin C found in fruits and vegetables measure far less than 1 gram.

Because of vitamin C’s ability to act as a potent antioxidant, vitamin C oral supplements were speculated to prevent cancer initiation. In 2004, researchers reported on the efficacy of 120 mg vitamin C supplementation for the prevention of cancer incidence, describing a randomized, double-blind, placebo-controlled primary prevention trial of 13,017 French adults. After a median time of 7.5 years, the subjects taking vitamin C supplements had lower total cancer incidence compared to controls. (41)

The anticancer mechanisms of vitamin C are different. Ascorbate oxidation produces hydrogen peroxide (H2O2) which has long been proposed to enhance H2O2-mediated tumor cell killing. (42) Ascorbate oxidation occurs more readily in the presence of catalytic metals, including redox active iron, where ascorbate can act as a one-electron reducing agent and thereby reduce ferric (Fe3+) to ferrous (Fe2+) while producing an ascorbate free-radical. In the presence of oxygen, the ferrous iron resulting from the reaction with ascorbate can be oxidized to generate superoxide and the superoxide radical can then be dismuted by superoxide dismutase (SOD) to produce H2O2 and O2. The resulting H2O2 is the central cytotoxic product of high-dose ascorbate use.

I’ve long heard tales of H2O2 (hydrogen peroxide) therapy for cancer and have seen recommendations of oral use which I’ve firmly discredited. H2O2 must be created in vivo to affect a distant cancer and the use of higher dose vitamin C may be the solution as well as the explanation of the benefits cancer patients have seen over the decades.

In 2004, Riordan et al. performed a pilot study of pharmacological ascorbate in late-stage cancer patients diagnosed with renal cell carcinoma, colorectal cancer, pancreatic cancer, non-Hodgkin’s lymphoma, and breast cancer (43, 44). This study showed that gram dose intravenous ascorbate was safe and efficacious.

Dosing vitamin C orally may best best by using liposomal sources at 1-5 grams daily. Intravenous vitamin C usually starts at 15 grams, 1-3 times per week and can range up to 75 grams based upon weight and tolerance.

I love finding supportive documentation that justifies long recommended though poorly understood mechanisms in alternative cancer care. It is my joy to aide in even small ways to both help practitioners understand their therapies, the often paradoxical functions of nutrients, and help patients have confidence in their care.


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