File Name: cancer and vitamin c linus pauling .zip
The selective anticancer properties of vitamin C are known since at least four decades. However, only recently in vitro studies have shown that vitamin C, in high enough concentrations, can efficiently and selectively kill a number of different human tumor cell lines, and these data have been confirmed in experimental animal tumor models.
The first human clinical trials revealed that high doses of vitamin C administered by intravenous injection are not only very well tolerated but also substantially improve the quality of life of patients with clinically advanced cancer.
However, the clinical evidence of the effectiveness of vitamin C in fighting off cancer is still controversial. The present chapter outlines the importance of vitamin C for a number of physiological functions, within the human body, and shows that there is a solid rationale for its use in the routine treatment of cancer, either alone or in combination with conventional treatment.
Vitamin C. The anticancer effects of vitamin C ascorbic acid are known since , when Benade et al. A few years before this discovery, the American biochemist, Irwin Stone, had already published some interesting reports on the genetic origin of scurvy, the lethal disease produced by severe deficiency of vitamin C.
The long-term biochemical outcome of CSS, according to the scientist, sets the stage for the development of the serious medical problems of later life, including, among others, cardiovascular diseases CVDs , collagen diseases, and cancer. Clinical tests reveal that mega levels of vitamin C are useful in the prevention and treatment of cancer and other diseases. Moreover, to correct CSS at least 10 g of vitamin C per day depending upon the incident stresses is required.
The full correction of CSS is, therefore, the first step in any preventive medicine procedure. Even though the recommended dietary allowances RDA [ 2 ] prescribe daily amounts of vitamin C in the order of a few milligrams, these, according to Stone, will only prevent the appearance of the terminal symptoms of scurvy, but will not do much else.
The evidence that among the mammals producing their own vitamin C, an unstressed 70 kg goat is capable of producing 13 g of this liver metabolite, [ 5 ] and much more under stress had convinced Stone that vitamin C RDAs were largely underestimated. Therefore, he proposed the use of mega doses or doses ranging from to several thousand times, the amount suggested by the RDAs of the nutrient to treat and prevent different diseases including cancer [ 6 ].
However, although formally proposed by Stone, the therapeutic use of mega doses of vitamin C was not really a novelty. In , Frederick Klenner had reported the successful treatment of 60 cases of bulbar poliomyelitis, with high doses of vitamin C, administered by mouth and, simultaneously, by intramuscular and intravenous injection, continuously, for 72—96 hours, until the complete remission of the symptoms [ 7 ].
Klenner proposed his anti-Polio, vitamin C—based treatment after reading a series of studies published by Jungeblut, between and [ 8 ], but he also treated with success, a number of other viral diseases, by using the same high dose vitamin C protocol. Lack of ascorbic acid caused scurvy, so if there was no scurvy there was no lack of ascorbic acid.
Nothing could be clearer than this. The only trouble was that scurvy is not a first symptom of lack but a final collapse, a premortal syndrome, and there is a very wide gap between scurvy and full health … But nobody knows what full health is! This leads us into statistics, which demand organization. However, there is another, more individual difficulty. The twofold Nobel Laureate, Linus Pauling later formalized this concept, in an article published in [ 9 ]. In the same year, Cameron and Campbell published an article concerning the treatment of 50 patients with advanced cancer, with 10 g of vitamin C administered by vein for the first few days, and then by mouth, for the rest of their lives.
The results of this study indicated that high doses of vitamin C are useful as a routine supportive measure to reinforce standard treatment of earlier and more favorable cases [ 10 ]. Two years later, Cameron and Campbell demonstrated that the use of the protocol proposed by Cameron and Pauling significantly prolonged the survival and improved the quality of life of terminal cancer patients [ 11 ], but their work raised a number of criticisms, especially focused on the randomization procedure.
To respond to the critics, the authors decided to undertake a second investigation, but this new study further confirmed that patients on mega doses of vitamin C lived, on average, days longer than the untreated controls [ 12 ]. The same authors [ 13 ] and a group of Japanese clinicians [ 14 ] later confirmed the results formerly obtained by Cameron and Pauling.
In an attempt to either duplicate or refute the results reported by Cameron and Pauling, the Mayo Clinic initiated another investigation, which seemed to disprove the efficacy of the mega doses of vitamin C against cancer [ 15 ]. However, according to Pauling, the inclusion criteria used by the Mayo Clinic scientists were not conformed to the ones he had used.
In fact, the Mayo Clinic study included patients previously treated with chemotherapy that compromises the immune response, while a functioning immune system is, according to Pauling, a fundamental prerequisite for an effective anticancer action of mega doses of vitamin C.
Therefore, based on this and other criticisms, the Mayo Clinic group undertook a second clinical investigation that substantially confirmed the results of the first one [ 16 ], and this study represented, for the scientific community, the definitive evidence of the inefficacy of mega doses of vitamin C against cancer.
As an undoubted evidence of the biases affecting this study, it will be worth mentioning that the second clinical trial performed at Mayo included only patients affected by colorectal cancer CRC , that are clearly not representative of the entire complex and variegated range of cancer types affecting humans. However, to remain confined to just CRC as a paradigm of cancer, it will be worth mentioning the recent reports showing that vitamin C in high doses kills BRAF and KRAS mutants of CRC, which are resistant to the standard chemotherapeutic regimens, thus, substantially disproving the results of the second Mayo Clinic investigation [ 17 — 19 ].
Vitamin C is an essential nutrient with a number of beneficial functions, for the organism, since it. Vitamin C is ubiquitous, but humans, guinea pigs, some primates, a particular type of fruit-eating bat, the majority of fishes and birds do not produce it, and therefore they depend on diet for the assumption and use of this fundamental nutrient [ 20 ].
Regarding the anticancer properties of vitamin C, different authors have proposed various mechanistic explanations; among others:. As mentioned in the previous section, the hypothesis that vitamin C in high concentrations, administered by intravenous infusion, acts as a prooxidant, rather than antioxidant, leading to the formation of H 2 O 2 , with consequent oxidative damage to cancer cells, was formerly proposed in [ 1 ].
According to this hypothesis, vitamin C kills cancer cells through the intracellular generation of toxic hydrogen peroxide H 2 O 2 produced upon its oxidation by the cells themselves. The theory was further investigated, very recently, by Yun et al.
Briefly, vitamin C in high doses administered by intravenous injection exerts its selective cytotoxic effect on cancer cells, because, after parenteral administration, it behaves as a peroxide delivery system for the generation of sustainable ascorbate radical and H 2 O 2 in the extracellular space, with consequent oxidative damage to cancer cells Figure 1. The selectivity of the cytotoxic effect of parenteral vitamin C depends on the fact that cancer cells, compared to their normal counterpart, show a reduced level of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase.
The reduced level of antioxidant enzymes leads to cellular damage by accumulation of H 2 O 2 , with consequent intracellular redox imbalance and oxidative damage to different cellular structures. Prooxidant effect of vitamin C see text. Legend: Vit. Yun et al. In summary, the data reported by Yun et al. DHAA is then reduced again to vitamin C inside the cells. Oxidative stress, in turn, leads to inactivation of GAPDH, inhibition of glycolysis, and energetic crisis, which leads to cancer cell death.
According to this mechanistic explanation, vitamin C, functioning as a prooxidant, would induce an increase in the intracellular reactive oxygen species ROS , which leads to increased DNA damage, with consequent activation of poly ADP-ribose polymerase PARP , an enzyme necessary to repair damaged DNA. The theory according to which vitamin C in high doses would act as a prodrug of H 2 O 2 , beyond being criticized by different authors, seems somewhat controversial and overlooks a few important aspects as follows:.
Although reported in by Chen et al. Interestingly, while according to Benade, H 2 O 2 forms inside the cell, starting from vitamin C, Chen et al. H 2 O 2 is a metabolite normally produced by the cells of the body and usually overproduced by cancer cells. Therefore, H 2 O 2 itself could be an optimal substitute for vitamin C, as an anticancer compound. The time for complete disappearance of the tumor varied from 15 to 50 days depending on the tumor size at the beginning of treatment.
As a consequence, an in vivo measurement of catalase activity in tumors would represent a useful diagnostic tool to predict which cancers will respond to pharmacological doses of vitamin C therapy or H 2 O 2 [ 29 ]. According to the prooxidant theory, vitamin C in high concentrations induces the production of H 2 O 2 through a Fenton-like reaction Figure 4. This reaction is the oxidation of organic substrates by iron and hydrogen peroxide.
Cancer cells produce high amounts of H 2 O 2 , and high levels of this metabolite have been associated with key features in cancer, such as DNA alterations, cell proliferation, apoptosis resistance, metastatic spread, angiogenesis, and hypoxia-inducible factor 1 HIF-1 activation. On the contrary, decreasing the cellular levels of H 2 O 2 may reverse the malignant phenotype. Therefore, H 2 O 2 can be either proapoptotic or antiapoptotic, either carcinogenic or anticarcinogenic, depending on its concentration and localization within the cell [ 32 , 33 ];.
However, some literature data seem to demonstrate that the exact opposite is true. In particular, Mojic et al. According to these authors, iron at physiological concentrations promotes both production and decomposition of H 2 O 2 , the latter being mediated by a Fenton reaction, which prevents the accumulation of H 2 O 2 , thus abolishing the cytotoxic effect of vitamin C.
To repeat in vivo the results obtained in vitro , the authors suggest that the simultaneous administration of vitamin C and chelating agents remove iron [ 34 ]. Vitamin C ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide, and catalytic metals accelerate the oxidation process.
This means that catalytic iron is not strictly necessary for the production of H 2 O 2 , starting from vitamin C, and therefore, the Fenton reaction may not be essential for this purpose. The autoxidation, i. In particular, that at pH 7. In most laboratory settings, autoxidation of vitamin C is due to adventitious catalytic metals, as part of the buffers used or contaminating of lab equipment.
Both the antioxidant and prooxidant activities of vitamin C in high doses may not necessarily be mutually exclusive. Studies on chelation therapy have shown that 5 g of the sodium salt of vitamin C added to the ethylenediaminetetraacetic acid EDTA chelation cocktail results in acute oxidative stress, but this effect is transitory, and after multiple sessions of EDTA-based chelation treatment, a prolonged, protective, antioxidant effect of the treatment becomes evident [ 37 ].
These data confirm the evidence reported by Mojic et al. Flow cytometric analysis of Y79 human retinoblastoma cell line viability, after treatment with increasing concentrations of vitamin C Asc in vitro. D: Contrast phase microphotograph of Y79 human retinoblastoma cell lines after treatment with vitamin C 7 mM. At a concentration of 7 mM, vitamin C destroys the vast majority of cells in culture.
Fenton reaction mediated by vitamin C. In summary, increasing the concentration of vitamin C with mega doses of the nutrient injected in vein may lead to a substantial increase in the spontaneous generation of H 2 O 2 , with toxic consequences to cancer cells, according to the chain of biochemical reactions more recently described by Yun et al.
This does not mean that the administration of vitamin C in high doses by intravenous injection abrogates its antioxidant properties, but most probably that both prooxidant and antioxidant effects coexist.
It rather implies that both antioxidant and prooxidant properties are simultaneously present in the molecule, the latter resulting more pronounced when the concentration of the nutrient reaches values in the order of millimoles 20 mM. Many of the symptoms of scurvy the syndrome of acute deficiency of vitamin C depend on the defective production of collagen. Since the beginning of the history of this nutrient, scientists know that vitamin C is essential for the synthesis of collagen.
Indeed, vitamin C is a cofactor of collagen prolylhydroxylase C-P4H , the enzyme responsible for the formation of hydroxyproline, the essential component of collagen. Under conditions of vitamin C deficiency, C-P4H loses its activity, and the organism does not form collagen properly, with consequent connective tissue deterioration, as it happens in scurvy Figure 4. Prolyl-hydroxylases are an entire family of enzymes, also known as 2-oxoglutarate-dependent dioxygenases 2-OGDDs with a wide range of biological functions [ 39 ], and members of this family include HIF-hydroxylases [ 40 ].
These vitamin C—dependent enzymes are of extreme importance in tumor biology since hypoxia and induction of HIFs are a hallmark of many tumors [ 41 ]. HIF is a heterodimeric transcription factor discovered in [ 42 ]. Recently, Kuiper et al. For a better understanding of the centrality of the relationship between hypoxia and HIF in tumor biology, we must consider that cancer hypoxia a very common feature in cancer is associated with HIF activity that mediates angiogenesis, epithelial-mesenchymal transition EMT , stem cell maintenance, invasion, metastasis, and resistance to radiation therapy and chemotherapy [ 48 ].
Therefore, attempts to downregulate HIF synthesis and activity may represent a step forward in the search of an effective and selective anticancer drug [ 49 , 50 ]. The current evidence shows that vitamin C has a close relationship with the function of HIF, and therefore, being a natural compound, it is the best-suited, natural molecule for the purposes of inhibiting cancer growth through HIF-mediated mechanisms.
Tian et al. Further important insights into the role of HIF have come from studies of three tumorigenic models in vivo , showing that the antitumorigenic effects of antioxidants such as N-acetylcysteine NAC and vitamin C are not due to their ability to squelch DNA damage and genomic instability mediated by ROS but due to their capacity to downregulate HIF levels [ 52 ].
Whether we consider its prooxidant activity, leading to cancer cell damage through the generation of H 2 O 2 or its antioxidant more typical activity, leading to the enzymatic breakdown, and nonenzymatic downregulation of the HIF, vitamin C in high doses always shows the characteristics of a simple, natural, and effective anticancer molecule;.
Vitamin C and other antioxidants may have a role as adjuvant therapy to prevent progression or recurrence of HIF-dependent tumors;. Vitamin C may show anticancer properties even when administered by mouth, with caution about the dose, which must be sufficiently high. Recent investigations have shown that ascorbate therapy has a significant effect on the expression of several genes relevant to the development or inhibition of cancer.
Vitamin C megadosage is a term describing the consumption or injection of vitamin C ascorbic acid in doses well beyond the current Recommended Dietary Allowance of 90 milligrams per day, and often well beyond the tolerable upper intake level of 2, milligrams per day. Pauling argued that because humans lack a functional form of L-gulonolactone oxidase , an enzyme required to make vitamin C that is functional in most other mammals, plants, insects, and other life forms, humans have developed a number of adaptations to cope with the relative deficiency. These adaptations, he argued, ultimately shortened lifespan but could be reversed or mitigated by supplementing humans with the hypothetical amount of vitamin C that would have been produced in the body if the enzyme were working. Vitamin C megadoses are claimed by alternative medicine advocates including Matthias Rath and Patrick Holford to have preventive and curative effects on diseases such as cancer and AIDS ,   but the available scientific evidence does not support these claims. Vitamin C is an essential nutrient used in the production of collagen and other biomolecules, and for the prevention of scurvy. Since its discovery, vitamin C has been considered almost a panacea by some,  although this led to suspicions of it being overhyped by others. The evidence for these claims is mixed.
Vitamin C L-ascorbic acid is a potent reducing agent, meaning that it readily donates electrons to recipient molecules Figure 1. Vitamin C is the primary water-soluble, non-enzymatic antioxidant in plasma and tissues. Even in small amounts, vitamin C can protect indispensable molecules in the body, such as proteins , lipids fats , carbohydrates , and nucleic acids DNA and RNA , from damage by free radicals and reactive oxygen species ROS that are generated during normal metabolism , by active immune cells, and through exposure to toxins and pollutants e. Vitamin C also participates in redox recycling of other important antioxidants; for example, vitamin C is known to regenerate vitamin E from its oxidized form see the article on Vitamin E. The role of vitamin C as a cofactor is also related to its redox potential.
January 24, , by Lewis Cantley and Jihye Yun. Lewis Cantley received his Ph. Jihye Yun received her Ph. The discovery and isolation of vitamin C was one of the most important advances in improving human nutrition. Scurvy, a severe vitamin C deficiency disease characterized by weakness, lethargy, easy bruising and bleeding, was particularly problematic for sailors on long voyages during the 16th century, where access to fresh fruits and vegetables was limited.
High doses of vitamin C, given every day, without ever stopping, to patients with cancer, as an adjunct to appropriate conventional therapy, improve the general health of nearly every cancer patient, increase survival time somewhat, and have great value for a fortunate few, who respond especially well. Most users should sign in with their email address. If you originally registered with a username please use that to sign in. To purchase short term access, please sign in to your Oxford Academic account above. Don't already have an Oxford Academic account?
I have, however, formulated the hypothesis which has not yet been tested by experiment that the effectiveness of ascorbic acid in providing protection against viral diseases results from its function in the synthesis and activity of interferon in preventing the entry of virus particles into the cells. The discovery of interferon was reported in by Isaacs and Lindenmann. It is a protein that is produced by cells infected by a virus and that has the property of spreading to neighboring cells and changing them in such a way as to enable them to resist infection. In this way the interferon ameliorates the disease. I estimate that for many people 1 g [gram] to 2 g per day mg to mg per day is approximately the optimum rate of ingestion.
The selective anticancer properties of vitamin C are known since at least four decades. However, only recently in vitro studies have shown that vitamin C, in high enough concentrations, can efficiently and selectively kill a number of different human tumor cell lines, and these data have been confirmed in experimental animal tumor models. The first human clinical trials revealed that high doses of vitamin C administered by intravenous injection are not only very well tolerated but also substantially improve the quality of life of patients with clinically advanced cancer. However, the clinical evidence of the effectiveness of vitamin C in fighting off cancer is still controversial. The present chapter outlines the importance of vitamin C for a number of physiological functions, within the human body, and shows that there is a solid rationale for its use in the routine treatment of cancer, either alone or in combination with conventional treatment. Vitamin C.
Vitamin C, Linus Pauling was right all along.
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