thiamine cancer

A Role for Thiamine Deficiency in Cancer

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There is ever increasing evidence that energy metabolism is involved in the causation of cancer. A phenomenon known as the Warburg effect has been known for a century and was thought by Warburg to be the cause of cancer. To summarize this effect, normal cells primarily produce energy by the consumption of oxygen in a complex mechanism known as oxidative phosphorylation. This involves the consumption of glucose as fuel. The Warburg effect is because most cancer cells produce energy through a high rate of glucose metabolism by fermentation, even though there is abundant oxygen present. This is a less efficient method of producing energy, an effect that has been much studied but whose mechanism still remains unclear.

In cancer research today, the focus has been primarily on genetic mechanisms and the Warburg effect is considered to be a result derived from these genetic changes rather than the underlying cause. However, energy is vital to normal cell function, so a drop in energy synthesis might be a defect that has a secondary effect on genetically determined mechanisms. Since the vitamin, thiamine, is so closely involved with the metabolism of glucose, it is not surprising that a few researchers have looked at the involvement of this vitamin in relationship to the cause of cancer. For this reason I turned to looking at what medical literature has been published in regard to this and was surprised to find that it was relatively abundant.

Wernicke’s Encephalopathy, Thiamine Deficiency, and Cancer

It has long been known that a deficiency of thiamine in part of the brain causes a brain disease that was named after the person who originally described it. This is known as Wernicke encephalopathy (WE). I discovered a manuscript in which 18 patients had developed WE during cancer treatment. Cancers involving blood cells and the gastrointestinal tract were reportedly more common, but poor appetite and weight loss were common risk factors. All of the 18 patients presented with cognitive dysfunction represented by impaired alertness, attention deficit and poor short-term memory. Few of these patients developed the typical symptoms described for the clinical diagnosis of WE, thus making it difficult to recognize the cause of the changes in the patient’s mental status. Of course, the obvious question is whether this is secondary to treatment or whether it is involved as part of the causative mechanism in the cancer. I looked for further evidence.

Breast Cancer and Thiamine Homeostasis

A group of researchers set out to try to find whether there was a difference in thiamine homeostasis (its overall place in body chemistry) in breast cancer cells as compared with normal breast tissue. Without going into the scientific details, they concluded that their findings demonstrated an adaptive response by breast cancer cells to increase cellular availability of thiamine, thus demonstrating its importance to those cells. To explore further the relationship of thiamine in breast cancer, female breast cancer genetically susceptible mice were exposed to 4 diets that varied in fat and thiamine content. The scientific discussion is complex but the authors concluded that there was a potential role for dietary thiamine and an interaction between thiamine and fat in breast cancer progression. This may be important since thiamine has recently been found to be involved in the metabolism of some fats. The findings of a study support the protective effects of thiamine, folate, riboflavin and vitamin B6 against breast cancer in general.

A compound by the name of dichloroacetate has been found to kill cancer cells in breast, brain, and lung cancers in rats, while not harming healthy cells. The anti-cancer effects of this drug have been reviewed. Without indicating the scientific aspects of the study, the authors noted that their findings, together with limited clinical results, suggest that there is a potentially fruitful area for clinical trials with some tumors. A study suggested that high-dose thiamine reduces cancer cell proliferation by a mechanism similar to that described for dichloroacetate.

Surgery, Thiamine Deficiency, and Wernicke’s Encephalopathy

Cancer patients submitted to gastrointestinal surgery are at risk for thiamine deficiency and WE. They often remain undiagnosed and untreated and WE may become manifest several months after hospital discharge. The authors stated that “even in the absence of symptoms of thiamine deficiency the use of prophylactic thiamine supplementation should be taken into consideration, as the consequences of misdiagnosis can be severe “.

With Cancer Genetic Research Dominates

A well-known proverb states that “there is never smoke without fire”. The questions raised in this post suggest that there is indeed “smoke”. There are several obvious reasons why the “smoke” is not being recognized sufficiently to jump start major research. The first reason is that it has been concluded that the Warburg effect is secondary to genetic cause. Genetic issues have therefore become virtually the exclusive approach. However, the available literature suggests that nutritional issues may have an epigenetic (how genes are affected by nutrients and lifestyle) relationship with genetic activity.

I would like to suggest a third issue, the impact of stress. A definition of stress states that it is a mental or physical force requiring brain/body defensive interaction, requiring an individual to adapt to the existing situation. It makes little difference whether the stress is mental or physical. It is the brain that has to conduct the orchestrated reactions. Chronic long-term mental stress is just as debilitating as prolonged  physical illness or severe trauma. The reasoning is derived from the work of Hans Selye. For those unfamiliar with this research, Selye stressed rats physically by many different types of assault. It is probable that his cruel experiments, performed over many years, made the recognition of his work much less acceptable. Nevertheless, he was able to determine that physically stressed animals went through several stages of resistance that he called the General Adaptation Syndrome (GAS). These stages were repetitive from animal to animal and were reflected by laboratory changes in tissues and blood similar to those seen in human disease.  Selye’s most interesting conclusion was that a great deal of energy was required in order to meet the physiological needs of resistance and that it was a failure of this energy synthesis that caused final collapse. Skelton, one of Selye’s students, was able to induce the GAS by making an animal thiamine deficient, thus demonstrating a relationship with energy metabolism. Selye offered the statement that human diseases were “diseases of adaptation”. His conclusion was more remarkable since little was known  during his time concerning the synthesis of energy in the human body. Much more is known now, making Selye’s work more plausible.

Preventing Illness

We cannot avoid the situations of life that give rise to chronic long-term mental stress. If our ability to handle them successfully depends on pristine nutrition, it obviously entails self-discipline as possibly our strongest preventive method. Physical stress may be lethal in its own right but nonlethal injury demands brain activity in coordinating the adaptive defense and is thus just as dependent on brain function. We now know that  consumption of energy is greatest in the heart and brain so perhaps it is not surprising that heart and brain disease are so common.

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This article was published originally on September 17, 2018. 

The Warburg Effect in Cancer

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In the 1930s Otto Warburg won a Nobel Prize for an observation that has since become known as “the Warburg effect” in oncology. He had reported that most cancer cells predominantly produce energy by a high rate of glycolysis (sugar metabolism) rather than the low rate in most normal cells. The energy in cancer cells, that typically have a glycolytic (sugar metabolism in action) rate up to 200 times higher than normal cells, is produced by fermentation. This form of energy production does not require oxygen and is known as anaerobic metabolism (without oxygen). Normal cells derive their energy from a chemical process that does require oxygen, hence the term oxidative, or aerobic (requiring oxygen), metabolism. The process of fermentation in cancer cells is much less efficient in producing energy than that in normal cells that derive energy from oxidative metabolism. Curiously, this anaerobic metabolism happens in cancer cells even when oxygen is plentiful. Although this has been much studied, its importance, either in cause or effect, remains unclear. Warburg had postulated that this change in metabolism is the fundamental cause of cancer, a claim now known as the Warburg hypothesis or Warburg effect. Today, mutations in oncogenes (genes associated with cancer) are thought to be responsible for malignant transformation and the Warburg effect is considered to be a result of these mutations rather than the cause. In other words, does the Warburg effect originate the cancer or is it an effect of the cancer? It is a typical “chicken and egg” question.

The Role of Thiamine in Cancer

The relationship between supplemental vitamins and various types of cancer has been the focus of recent investigation. Supplemental vitamins have been reported to modulate cancer rates and a significant association has been demonstrated between cancer and low levels of thiamine in the blood (1). This also gives rise to a “chicken and egg” question. Is the low level of thiamine a result of treatment using chemotherapy and radiation or does it have a causative relationship? Thiamine deficiency is increasingly recognized in medically ill patients. Its prevalence among cancer patients is unknown. However, thiamine deficiency was found in 119 (55.3%) of 217 patients with various types of cancer. Risk factors included effects of chemotherapy or undergoing active treatment (2). It is possible to induce a certain type of tumor in mice. Thiamine supplementation between 12.5 and 250 times the recommended dietary allowance (RDA for mice) stimulated the tumors. Doses 2500 times the RDA resulted in 10% inhibition of tumor growth (3). This inhibitory effect of exceedingly high doses of thiamine is unexplained and certainly merits further study.

Thiamine as a Drug

The definition of a drug is “a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body”. Therefore, if thiamine is taken as a supplement, it must be considered to be a drug. Conventional wisdom sees thiamine as a food-borne particle whose function, in a minute concentration, is to assist the enzymes to which it is attached. The daily dose is governed by the RDA and is stated as 1 to 1.5 mg/day. For this reason, if its deficiency as a cause of symptoms is recognized in a given patient, the treatment would be considered to be simply replacement value. Any increase in that dose would inevitably be considered completely unnecessary. This is in spite of the hard-won history that treating beriberi demanded as much as 100 mg of thiamine a day for months. Of course, as I have mentioned in these pages many times, conventional wisdom also denies that beriberi, or any other form of vitamin deficiency, exists in America or any other developed culture. There are now many reports in the medical literature of thiamine being used in megadoses to treat virtually any disease associated with or caused by a breakdown in energy metabolism. It is therefore worth considering the potential mechanism in the already established place of thiamine, or its derivatives, in cancer.

We used to think that our genes dominated our body functions in a fixed way throughout life. The relatively new science of epigenetics tells us that nutrition and lifestyle have a powerful influence on our genetically determined mechanisms. Research in cancer has been almost completely dominated by study of the influence of specialized genes, known as oncogenes. The question that should arise is what, if ever, is the influence of malnutrition on these genes. Could thiamine deficiency “turn on” or otherwise influence oncogenes through epigenetic mechanisms? Our book (Lonsdale D, Marrs C. Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition) emphasizes that widespread thiamine deficiency exists in America because of an inordinate ingestion of sugar in all its different forms. The book supplies evidence that an overload of glucose ingestion provides “empty calories” that overwhelms the capacity of thiamine metabolism in processing the glucose. In other words, the intake of thiamine in the diet might be sufficient for a normal calorie load but insufficient for the load of empty calories. This is referred to as “high calorie malnutrition”. Calibration of diet depends on a study of three meals a day. We suggest that it is the inordinate consumption of sugar associated with almost all social activities that may make the difference. We question whether there is a potential relationship with the increasing incidence of cancer. Is sugar our ultimate enemy? Is our hedonistic consumption of it a threat to our civilization? Although this sounds like a fictional idea for a novel, understanding the complex role of thiamine in glucose metabolism should make us pause to wonder whether the pleasure derived from taste is a potential cause of our undoing.

Hypoxia, Thiamine and Cancer

Hypoxia is one of the hallmarks of the tumor microenvironment (referring to the local concentration of oxygen that exists around cells that become cancerous). It is the result of insufficient blood supply to support growing tumor cells (4). This would result in lack of oxygen, but also would restrict the supply of vitamins, including thiamine. It is interesting that thiamine deficiency results in a metabolic disturbance that induces a state similar to deficiency of oxygen and is known as pseudo-hypoxia (pseudo-, meaning false)(5).

The term vitamin was derived from the finding that each one of these chemical substances found in naturally occurring food is “vital” to life. Thiamine’s role is to turn chemical food substances into energy. Therefore, it must be recognized as having the same life-giving effect in the body as oxygen. Granted that it is not the only vitamin required for this, however, it appears to have a degree of importance that makes it the dominant factor. Early studies of the relationship of thiamine deficiency as the cause of beriberi showed that, as the disease progressed, there were different metabolic patterns marking the degree of deficiency. For example, patients with a normal blood sugar responded to thiamine easily. Those with a high blood sugar were slower to respond and those with a low blood sugar often didn’t respond at all. The far-reaching consequences of the increasing effect of thiamine deficiency as the disease progressed need to be understood better.

It is known that the part of the brain that enables us to adapt to and thrive in our hostile environment, is particularly susceptible to thiamine deficiency. Therefore, its deficiency provides effects that are exactly similar to partial deprivation of oxygen. Is it possible that thiamine deficiency, resulting as it does in loss of efficient oxidative metabolism, is the underlying factor that initiates the cancer by an epigenetic mechanism? The low dose/high dose administration of thiamine in producing the opposite effects may be a mystery of thiamine metabolism requiring further research. Perhaps thiamine deficiency activates the genetic mechanisms that are known to be involved in the transition of the normal cell into a cancerous one. It may be that some cancers (and a lot of other diseases) could be prevented by a rational approach to a diet that spares us from metabolic stress induced by this highly artificial “high calorie malnutrition”.

Although this article is written for general readership, references are included to show that the statements made within the article are supported by publication in the medical literature.

References

  1. Lu’o’ng KV, Nguyen LT. The role of thiamine in cancer: possible genetic and cellular signaling mechanisms. Cancer Genomics Proteomics, 2013, 10 (4): 169-85.
  2. Isenberg-Grzeda, E., Shen, M. J., Alici, Y., Wills, J., Nelson, C., & Breitbart, W. High rate of thiamine deficiency among inpatients with cancer referred for psychiatric consultation: results of a single site prevalence study. Psychooncology 2016. May 26. doi. 10. 1002/pon. 4155. [Epub ahead of print]
  3. Comin-Anduix B, Boren J, Martinez S, et al. The effect of thiamine supplementation on tumor proliferation. A metabolic control analysis study Eur J Biochem, 2001, 268 (15): 4177-82.
  4. Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumor microenvironment. Immunology, 2014, 143 (4): 512-9.
  5. Sweet RL, Zastre JA. HIF1-α-mediated gene expression induced by vitamin B1 deficiency. Int J Vitam Nutr Res 2013, 823 (3): 188-97.

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