L-ascorbic acid (C6H8O6), known as Vitamin C, has a variety of functions in humans, some of which are not yet fully understood. It was discovered in 1930 by Albert Szent-Györgyi (Hungarian, half Romanian by descent), who as a result of this discovery received Nobel Prize in Physiology or Medicine in 1937. Note, that Albert Szent-Györgyi is the same scientist who about 20 years latter discovered the anti cancer effects of Methylglyoxal, discussed recently on this website in the following post https://www.cancertreatmentsresearch.com/?p=1471.
Vitamin C plays a vital role in the production of collagen, which is the principal connective tissue protein found in tendons, arteries, bone, skin and muscle. However, humans can not synthesize ascorbic acid due to the absence of the enzyme L-gulonolactone oxidase. Hence, in humans ascorbic acid has to be supplemented through food and/or as tablets. The two major forms of vitamin C in the diet are L-ascorbic acid and L-DHA. (Ref.)
Nobel laureate Linus Pauling began a long clinical collaboration with the British cancer surgeon Ewan Cameron in 1971 on the use of intravenous and oral vitamin C and as a result they proposed the use of high doses of ascorbic acid (> 10 g/day) to cure and prevent cold infections and in the treatment of cancer (Ref.).
The anti cancer mechanism suggested by Pauling and Cameron was essentially related to the tumor microenviroment. They argued that cells are normally restrained from proliferating by the highly viscous nature of the intercellular space and that cancer cells may escape from this due to an enzyme called Hyaluronidase which normally would be not there if enough Vitamin C would exist in the body. (Ref.1, Ref.2).
Its amazing how all things are connected. Just a few weeks ago I was discussing about Hyaluronidase in another post (https://www.cancertreatmentsresearch.com/?p=1489) and now I realize that Vitamin C has one of its major anti cancer mechanisms related to the same.
However, in addition to this mechanism, Vitamin C has other anti cancer actions highly relevant which also supports its use next to chemo therapy. Indeed, it is widely accepted now, at least within the scientific world, that while at lower concentrations Ascorbic Acid functions primarily as an antioxidant and can protect cells from oxidative stress, at higher concentrations Ascorbic Acid acts as a pro-oxidant that imposes oxidative stress and induces cell death (Ref.). The specific mechanism that leads to its pro oxidant anti cancer action will be discuses in more details below, in the “Mechanism” section.
In order to achieve the high dose required to exert its anti cancer action, Vitamin C has to be administrated intravenously. This is because when administrated orally, Vitamin C is absorbed only in very low amounts (Ref.). This low oral bio availability is also one of the reasons why some of the earlier clinical trials of Vitamin C in cancer have failed (Ref.).
As a side note, if intravenous administration is not an option, using liposomal vitamin C formulation may be a way to achieve same plasma levels of Vitamin C as that achieved via the intravenous route. Liposomal vitamin C can be bought online or formulated at home and administrated via the oral route. Here is a website where it is explained in detail how Liposomal vitamin C can be formulated at home http://qualityliposomalc.com/
Given its low toxicity and low cost, next to its serious anti cancer potential intravenous high dose Vitamin C was rapidly adopted by private clinics across the world to treat various disease including cancer. At the same time, academic research has been also preformed, indeed supporting the relevance of Vitamin C therapy in the the following areas:
- Heart Disease (Low dose Vitamin C) (Ref.1, Ref.2, Ref.3)
- High Blood Pressure (Ref.1, Ref.2)
- Common Cold
- Cancer (Ref.1, Ref.2., Ref.3 and many more)
- Reducing chemotherapy side effects (Ref.)
- Antiviral (Ref.)
- Treating allergy-related conditions, such as asthma, eczema, and hay fever (called allergic rhinitis)
- Decreasing blood sugar in people with diabetes
- Boosting immunity
- High-dose ascorbic acid was also recommended as a treatment in surgical critically ill patients with septic shock (Ref.)
After reviewing the literature, to me the following aspects are clear:
- There is enough scientific evidence to believe Vitamin C can kill cancer cells.
- Chemo sensitivity tests indeed indicate effectiveness of Vitamin C in about 70% of the tested cancer patients (see fig enclosed in the following post https://www.cancertreatmentsresearch.com/?p=1321)
- There are multiple reports published indicating anti cancer potential of Vitamin C in humans (see below section “Case reports in humans”)
However, it is also clear to me that when zooming-out and looking not at specific reports only but at large number of patients treated with high dose intravenous Vitamin C, the anti cancer effects become less visible (Ref.). Yes, some patients benefit from Vitamin C, a few are even cured, but many need to search for others options.
So my questions is: Why this conflicting evidence? Why in theory and laboratory experiments high dose Vitamin C seems to be effective for most tumor types while in real life is effective only for a few? Why some Vitamin C treatments are successful and other not in patients that all should respond to Vitamin C based on cancer type and e.g. chemosensitivity analysis?
Off course we can argue that even if it is effective for a few that is still highly relevant since we are speaking about life and about patients that are left with no options. But my question is what do we still need to understand and do in order to increase the success rate of high dose Vitamin C?
One simple answer to the above question can be related to the Vitamin C source. It can degrade relatively fast (becoming yellowish solution) and preparation just before administration may be the best.
I believe, a major answers may be found in this paper, published in 2014 in the prestigious journal Nature: Extracellular iron diminishes anticancer effects of vitamin C: An in vitro study http://www.nature.com/articles/srep05955.
Essentially, the article argues that that the anticancer/cytotoxic effects of Vitamin C are completely abolished by iron existent in the blood as the Vitamin C reacts with the Iron in the blood before reaching its target, i.e. the tumor, which would be the case for most of the patients. As a result, the authors suggest that in order to increase the chance of success of the Vitamin C therapy, the patient would have to be treated with Iron chelators prior to the Vitamin C therapy. The authorst suggested the use of Iron chelator such as Disulfiram (a safe and FDA approved drug used to support the treatment of chronic alcoholism), but other substances such as Baicalein, an extract from a plant named Scutellaria Barbata (known to also have anti cancer effects specifically in breast cancer) is also an Iron chelator (Ref.). Whole plant Scutellaria is available online as a supplement. On the same line, avoiding foods reach in Iron before/during Vitamin C therapy may be a good idea. Combining Vitamin C therapy with Gallium therapy may be another good idea. Using EDTA IV to chelate iron prior to Vit C IV may be yet another good idea (Ref.1, Ref.2).
Next to this, due to the mechanisms of action, I think there are a few more ways to improve the chance of success for high dose Vitamin C therapy, which I intend to discuss at the end of the “Mechanism” section of this post.
In conclusion, high dose Viatmin C (intravenous) has a great potential to fight cancer while being cheap, accessible and safe. As a result I would clearly consider it as a part of an anti cancer treatment strategy. However, according to the discussion above, in order to get the most out of it I would pay specific attention at the source, administration procedure and the whole treatment strategy around that.
Note: After publishing this post, I have received messages from readers asking if I am not positive about Vitamin C. I am actually positive and as a results we are using it. But with this post I intended to highlight not only the potential of Vitamin C but also the challenges we need to address in order to make use of its potential and be successful.
Update April 3rd, 2018: Thanks to Ergin for indicating this article “O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.” https://www.ncbi.nlm.nih.gov/pubmed/28366679 published in the Cancer Cell, one of the top scientific peer-reviewed journals reporting major advances in cancer research and oncology. This is a well researched article published in 2017 and co-authored by 35 medical doctors and scientists from USA stating the following:
“Despite advances in treatment strategies, 5-year overall survival in NSCLC and GBM has not significantly increased over the last 20 years. Here, we demonstrate that pharmacological ascorbate represents an easily implementable and non-toxic agent that may increase treatment efficacy when combined with standard-of-care radio-chemotherapy in NSCLC and GBM. Furthermore, the mechanism by which ascorbate is selectively toxic to cancer cells versus normal cells is shown to involve alterations in redox-active iron metabolism mediated by mitochondrial O2- and H2O2. As fundamental defects in oxidative metabolism leading to increased steady-state levels of O2- and H2O2 emerge as targetable hallmarks of cancer cells, the current findings support a generalized mechanism for the application of pharmacological ascorbate in cancer therapy.”
The above is an as clear statement as it can get n a scientific setting, coming from 35 medical doctors and scientists.
Successful case reports in humans:
Introduction. Intravenous high-dose vitamin C therapy is widely used in naturopathic and integrative oncology; however, a study reviewing its effects has never been performed in Singapore. This article serves to document administration of supportive vitamin C therapy for cancer patients in Singapore. Methods. The clinical response of 9 cancer patients of differing stages to the regular administration of large doses (25-100 g/d) of intravenous vitamin C (IVC; ascorbic acid) is outlined. Tumor pathology and patient health were verified by doctors who do not practice vitamin C treatment. Results. Cases suggesting survival beyond prognosis, improvement in quality of life, safe coadministration with and improved tolerance of conventional therapy, and deterioration in clinical condition following withdrawal of vitamin C therapy are documented clinically. Some patients experience the Jarisch-Herxheimer reaction—the release of endotoxin from microorganism death resulting in pimples, fever, and body odor—for a few hours after the therapy, but these are resolved quickly with no lasting effects. Conclusion. Randomized trials of IVC therapy are recommended because it has minimal side effects and has shown promising results.
Intravenously administered vitamin C as cancer therapy: three cases http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1405876/
Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 μmol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50–100 g) given intravenously may result in plasma concentrations of about 14 000 μmol/L. At concentrations above 1000 μmol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.
A case report from Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, published at the end of 2015:
We report a case of regression of multiple pulmonary metastases, which originated from hepatocellular carcinoma after treatment with intravenous administration of high-dose vitamin C. A 74-year-old woman presented to the clinic for her cancer-related symptoms such as general weakness and anorexia. After undergoing initial transarterial chemoembolization (TACE), local recurrence with multiple pulmonary metastases was found. She refused further conventional therapy, including sorafenib tosylate (Nexavar). She did receive high doses of vitamin C (70 g), which were administered into a peripheral vein twice a week for 10 months, and multiple pulmonary metastases were observed to have completely regressed. She then underwent subsequent TACE, resulting in remission of her primary hepatocellular carcinoma. http://www.ncbi.nlm.nih.gov/pubmed/26256994
Here is an article published in 2000 including several case reports, most of which lead to complete remission:
- A case report on adenocarcinoma of his right kidney: One of us (HDR) reported positive effects of vitamin C therapy in a patient with adenocarcinoma of the kidney in 1990.4 This report described a 70-year-old white male diagnosed with adenocarcinoma of his right kidney. Shortly after right nephrectomy, he developed metastatic lesions in the liver and lung. The patient elected not to proceed with standard methods of treatment. Upon his request, he began intravenous vitamin C treatment, starting at 30 grams twice per week. Six weeks after initiation of therapy, reports indicated that the patient was feeling well, his exam was normal, and his metastases were shrinking. Fifteen months after initial therapy, the patient’s oncologist reported the patient was feeling well with absolutely no signs of progressive cancer. The patient remained cancer-free for 14 years. He died of congestive heart failure at the age of 84.
- Another case report in metastatic renal cell carcinoma patient publish in 1998: The patient was a 52-year-old white female from Wisconsin diagnosed with non-metastatic disease in September 1995. In October 1996, eight metastatic lung lesions were found: seven in the right lung and one in the left (measuring between 1-3 cm). The patient chose not to undergo chemotherapy or radiation treatments. The patient was started on intravenous vitamin C and specific oral nutrient supplements to correct diagnosed deficiencies and a broad-spectrum oral nutritional supplement in October, 1996. The initial dose of intravenous vitamin C was 15 grams, subsequently increased to 65 grams after two weeks. The patient was given two infusions per week. Intravenous vitamin C treatments were continued until June 6, 1997. An x-ray taken at that time revealed resolution of all but one lung metastases. The patient discontinued intravenous vitamin C infusions at that time and continued taking the broad-spectrum oral nutritional supplement. A radiology report on a chest x-ray taken January 15, 1998, stated that no significant infiltrate was evident, and there was resolution of the left upper lobe lung metastasis. In February, 1999 a chest xray showed no lung masses, and the patient reported being well at that time.
- for more case reports please read the following reference http://www.orthomolecular.org/library/jom/2000/pdf/2000-v15n04-p201.pdf
A 12 Week, Open Label, Phase I/IIa Study Using Apatone® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy http://www.medsci.org/v05p0062.htm
Purpose: To evaluate the safety and efficacy of oral Apatone® (Vitamin C and Vitamin K3) administration in the treatment of prostate cancer in patients who failed standard therapy.
Materials and Methods: Seventeen patients with 2 successive rises in PSA after failure of standard local therapy were treated with (5,000 mg of VC and 50 mg of VK3each day) for a period of 12 weeks. Prostate Specific Antigen (PSA) levels, PSA velocity (PSAV) and PSA doubling times (PSADT) were calculated before and during treatment at 6 week intervals. Following the initial 12 week trial, 15 of 17 patients opted to continue treatment for an additional period ranging from 6 to 24 months. PSA values were followed for these patients.
Results: At the conclusion of the 12 week treatment period, PSAV decreased and PSADT increased in 13 of 17 patients (p ≤ 0.05). There were no dose-limiting adverse effects. Of the 15 patients who continued on Apatone after 12 weeks, only 1 death occurred after 14 months of treatment.
Conclusion: Apatone showed promise in delaying biochemical progression in this group of end stage prostate cancer patients.
High-Dose Intravenous Vitamin C Combined with Cytotoxic Chemotherapy in Patients with Advanced Cancer: A Phase I-II Clinical Trial http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388666/
Phase I clinical trial of i.v. ascorbic acid in advanced malignancy http://annonc.oxfordjournals.org/content/19/11/1969.full
Two patients at the 0.6-g/kg dose (one with prostate cancer and the other with epidermoid carcinoma) received greater than six cycles of ascorbic acid with stable disease (less than a 20% reduction and less than a 20% increase in the sum of the two perpendicular diameters of the target lesion and the appearance of no new lesions).
Numerous reports are available in literature on cytotoxic and anti-carcinogenic effect of ascorbic acid and its derivatives in different tumor model systems. However, the molecular mechanisms underlying the anti-carcinogenic potential of ascorbic acid are not completely elucidated. Below are some of the major mechanisms that may be associate with anti-carcinogenic effect of ascorbic acid:
- Pauling and Cameron believed that the mechanism behind the anti cancer activity of Vitamin C is the following:
- Cells are normally restrained from proliferating by the highly viscous nature of the intercellular space.
- In order to proliferate, cells must escape from this restraint by depolymerizing the glycosaminoglycans (including Hyaluronic acid) in their immediate environment.
- This process is accomplished by the release of the enzyme hyaluronidase and is kept in check by physiological hyaluronidase inhibitor.
- Hyaluronidase inhibitor is an oligoglycosaminoglycan that requires ascorbic acid for its synthesis, and perhaps incorporates residues of ascorbic acid. Note that the role of Hyaluronic acid in cancer was specifically discussed in a previous post on this website https://www.cancertreatmentsresearch.com/?p=1489 The authors argued that this hypothesis provides an explanation for the pathogenesis of scurvy. It explains the increased requirement for ascorbic acid that occurs in many cell proliferative diseases, including cancer. It indicates the existence of a basic underlying mechanism in many pathological states and suggests a common pattern of treatment. (Ref.)
- Therefore providing Vitamin C, oligoglycosaminoglycan inhibits Hyaluronidase and cancer cells remain isolated, and at some point die.
- The second major mechanism refers to the pro oxidant action of Vitamin C and is the following:
- Epithelial tumors appear to rely on superoxide (inflammation) which is produced by non-neoplastic stromal cells (Ref.) to oxidize the ascorbic acid (AA) to DHA (Ref.).
- Because of the structural resemblance of dehydroascorbic acid (DHA, the oxidized form of vitamin C) to glucose, DHA can enter the tumor cells through the GLUT transporters and accumulate inside (Ref.).
- When dehydroascorbate acid enters cancer cells, glutathione turned the dehydroascorbate back into ascorbic acid (vitamin C), which is not allowed to move out of cancer cells, i.e. is not transportable through the bidirectional GLUTs.
- This by itself is an anti cancer mechanims as the conversion of AA in DHA will consume glutathione required in the cancer cell to cope with the usual high levels of ROS in cancer cells
- This ascorbic acid is converted to dehydroascorbate again and produces H2O2, which destroy cancer cells (via reaction with the elevated Cooper (Ref.) and Iron concentrations in tumors, leading to generation of ROS).
- Other relevant mechanisms:
- high doses of ascorbate can reduce inflammatory cytokine levels in cancer patients
- Antiangiogenesis effects: Suppression of NO (nitric oxide) generation appeared to be one of the mechanisms by which AA mediated angiostatic effects (Ref.)
As promised above here are a few more ideas to improve the effectiveness of Vitamin C (next to the iron chelation):
- prior to Vitamin C administration, increase blood oxygen in order to support the AA conversion to DHA (e.g. ozon theraphy, etc.)
- avoid sugar prior to Vitamin C administrations in order to potentially activate even more GLUT1 receptors through which DHA enters cancer cells
- avoid any potential GLUT1 inhibitors prior to Vit C administration
- avoid anti oxidant therapies around Vit C administration
- include pro oxidant therapies such as 3BP, DCA, etc.
Hoffer, et al. reported that when 1.5 g/kg of vitamin C was administered in humans, plasma concentrations over 10 mM could be maintained for 4.5 hours (Ref.)
Other relevant points:
- pH influences the stability of ascorbic acid. It exhibits maximal stability between pH 4 and 6 (Ref.)
- DHA is very unstable. DHA taken up or generated in the matrix must be reduced back to ascorbate, otherwise, in physiological conditions, it is lost within minutes.
High-dose vitamin C therapy should be avoided in patients with renal failure or renal insufficiency, and in patients undergoing dialysis (Ref.).
Due to the chelating effect of IVC, some patients may complain of shakiness due to low calcium or magnesium. An additional 1.0 mL of MgCl added to the IVC solution will usually resolve this. If severe, it can be treated with an IV push of 10 mL’s of calcium gluconate, 1.0 mL per minute. (Ref.)
Combining a glycolisis inhibitor such as Vit C, with a mitochondria inhibitor such as Doxycicline seems to lead to great anti cancer effectiveness: “Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)” (Thanks Alternmed for the reference.)
IV Vitamin C Dose and Administration:
In General, Vitamin C is administrated at a dose of about 1.5g/kg/day, or in a range between 50g and 100g/day. Usually it is started at a lower level, at about 15g/day and increased during a few administrations to the target dose. In general, it is administrated 2 to 3x/week but for active cancers, an initial recommendation of 21 days of daily IVC therapy is used by some (Ref.).
The Vitamin C solution is pushed in an IV bag and administrated at a rate of 0.5 g/min so that 50g will be administrated during 100 min. Rates up to 1.0 gram/minute are generally tolerable, but close observation is warranted. Patients can develop nausea, shakes, and chills. (Ref.)
For reference, 50g Vitamn C are administrated in 50o ml IV bag and 100g Vitamn C in a 1000 ml IV bag. Some clinics are using NaCl IV bag but in general it is recommended that for doses greater than 15 g, the diluent should be sterile water to achieve a theoretical osmolarity between 500 and 900 mOsm/L (Ref.).
Sodium ascorbate is clear and dehydroascorbate is yellow – so if the solution turn yellowish it means sodium ascorbate started to degrade. To avoid the degradation during the IV administration, the IV bag should be warped in an opaque foil such as aluminium foil (in case it is not already opaque.
Here is a good administration protocol discussion: Vitamin C Research – IVC Protocol https://riordanclinic.org/research-study/vitamin-c-research-ivc-protocol/
Note: Sometimes combined with DMOS & B17 in the same bottle – “Manner Cocktail”
- E.g. 9 grams of Laetrile [Amygdalin/ B-17], 25-50 grams of Ascorbic acid [vitamin C], 10-15 ml. of DMSO (Ref.)
Kansas University: https://drive.google.com/file/d/0B_EpU6QZ4EZtYWhFZEIxZGF6eEk/view?usp=sharing
(Thank you to my friend Fred for the links above, on the various protocols)
Here is an example of a treatment protocol when Vitamin C was used in combination with chemo therapy:
“The IVC infusion protocol was previously described ; it is based on a well-known protocol developed by Riordan et al [43,44]. Vitamin C infusates were prepared using ascorbic acid 500 mg/mL for injection USP (supplied as single-use 50 mL glass ampules) as a gift from Alveda Pharma Canada, Ltd. The stock solution was diluted in sterile water to achieve an osmolarity of approximately 900 mOsm/L. Any air bubbles formed during preparation were promptly evacuated. The solutions were delivered to the clinical research unit covered by an opaque bag, allowed to come to ambient temperature, and infused by calibrated infusion pump within one hour of preparation. Water and other drinks (preferably sugar-free) were provided and the patients encouraged to consume them freely before, during and after IVC infusions. The dose of vitamin C was 1.5 g/kg body weight when the body mass index (BMI) was 30 kg/m2 or less, and normalized to the body weight corresponding to BMI 24 kg/m2 for patients with a BMI > 30. The vitamin was infused at a constant rate over a period of 90 minutes for doses up to 90 g, and over a period 120 minutes for doses > 90 g. IVC was infused three times (at least one day apart) on week days during weeks when chemotherapy was administered (but not on the same day as intravenous chemotherapy) and any two days at least one day apart during weeks when no chemotherapy was given.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388666/
Most compounding pharmacies including those listed here: https://www.cancertreatmentsresearch.com/?page_id=945
The price for a 25g vial – solution for IV – is around 15 to 20 euro.
If ready made IV Vitamin C is not available, the IV solution can also be formulated “in house”:
Dr. Cathcart’s youtube lecture on IV/C prep is the best tutorial on “do it yourself” IV/C. https://www.youtube.com/watch?v=Zgi-7xPrCAg And an updated version of his written document: http://www.vitamincfoundation.org/pdfs/civprep.pdf
One of the best Vitamin C powder to be formulated for IV usage seems to be Quali-C brand. If there are better suggestions on other brands please let me know.
The best is to formulate before the administration http://www.ncbi.nlm.nih.gov/pubmed/9760591
On the cytotoxicity of vitamin C and metal ions http://onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1983.tb07804.x/full
Cameron E, Pauling L: Ascorbic acid and the glycosaminoglycans. http://www.karger.com/Article/Abstract/224733
A new concept of a basic mechanism involved in cell proliferation is presented. It is suggested that cells are normally restrained from proliferating by the highly viscous nature of the intercellular . In order to proliferate, cells must escape from this restraint by depolymerizing the glycosaminoglycans in their immediate environment. This process is accomplished by the release of the enzyme hyaluronidase and is kept in check by physiological hyaluronidase inhibitor. There is some evidence that physiological hyaluronidase inhibitor is an oligoglycosaminoglycan that requires ascorbic acid for its synthesis, and perhaps incorporates residues of ascorbic acid. This hypothesis provides an explanation for the pathogenesis of scurvy. It explains the increased requirement for ascorbic acid that occurs in many cell proliferative diseases, including cancer. It indicates the existence of a basic underlying mechanism in many pathological states and suggests a common pattern of treatment. We conclude that ascorbic acid may have much greater therapeutic value than has been generally assigned to it.
Vitamin C in human health and disease is still a mystery? An overview https://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-2-7
Stromal cell oxidation: a mechanism by which tumors obtain vitamin C. http://www.ncbi.nlm.nih.gov/pubmed/10493506
Human tumors may contain high concentrations of ascorbic acid, but little is known about how they acquire the vitamin. Certain specialized cells can transport ascorbic acid directly through a sodium ascorbate cotransporter, but in most cells, vitamin C enters through the facilitative glucose transporters (GLUTs) in the form of dehydroascorbic acid, which is then reduced intracellularly and retained as ascorbic acid. Mice with established hematopoietic and epithelial cell xenografts were studied for the accumulation of injected ascorbic acid and dehydroascorbic acid. Most hematopoietic and epithelial tumor cell lines can only transport vitamin C in the oxidized form (dehydroascorbic acid) in vitro; however, when grown as xenografts in mice, they rapidly accumulated vitamin C after administration of radiolabeled ascorbic acid. The involvement of the GLUTs in vitamin C uptake by the xenografted tumors was demonstrated by competitive inhibition with D-glucose but not L-glucose. Because the malignant cells were not capable of directly transporting ascorbic acid, we reasoned that the ascorbic acid was oxidized to dehydroascorbic acid in the tumor microenvironment. Tumor accumulation of vitamin C in animals injected with ascorbic acid was inhibited by coadministration of superoxide dismutase, implying a role for superoxide anion in the oxidation of ascorbic acid. Whereas the epithelial cancer cell lines could not generate superoxide anion in culture, the minced xenograft tumors did. Our studies show the transport of dehydroascorbic acid by GLUTs is a means by which tumors acquire vitamin C and indicate the oxidation of ascorbic acid by superoxide anion produced by cells in the tumor stroma as a mechanism for generating the transportable form of the vitamin.
Intravenously administered vitamin C as cancer therapy: three cases http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1405876/
Cancer and vitamin C: a discussion of the nature, causes, prevention, and treatment of cancer with special reference to the value of vitamin C http://agris.fao.org/agris-search/search.do?recordID=US8128113
Aspects of the nature, causes, prevention and treatment of cancer are examined with emphasis on the value of vitamin C. The view is put forward that routine high intakes of ascorbic acid play a role in cancer by increasing the natural resistance of the patient; resistance of healthy tissues to metastasis by a malignant tumor may be the most important element in cancer progress and outcome. Extension evidence (clinical trials and case histories) supporting a therapeutic role for vitamin C in cancer treatment, especially if begun early, is presented. Increased ascorbate intakes by healthy individuals may also act to prevent the development of cancer. A discussion of the mechanisms of action of vitamin C, including its function in the immune system, provides insight into how the vitamin may work in the prevention and treatment of cancer
Vitamin C, Linus Pauling was right all along. A doctor’s opinion http://www.medicalnewstoday.com/releases/12154.php
Anti-cancer effects of vitamin C revisited http://www.nature.com/cr/journal/v26/n3/full/cr20167a.html
Vitamin C was first suggested to have cancer-fighting properties in the 1930s and has been the subject of controversy ever since. Despite repeated reports of selective cancer cell toxicity induced by high-dose vitamin C treatment in vitro and in mouse models, the mechanism of action has remained elusive.
Vitamin C injections ease ovarian-cancer treatments http://www.nature.com/news/vitamin-c-injections-ease-ovarian-cancer-treatments-1.14673
A clinic, expect in Vitamin C administration: https://riordanclinic.org/research-studies/
Ascorbic Acid and a Cytostatic Inhibitor of Glycolysis Synergistically Induce Apoptosis in Non-Small Cell Lung Cancer Cells http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067081#pone.0067081-Chen2
Vitamin C halts growth of aggressive forms of colorectal cancer in preclinical study http://meyercancer.weill.cornell.edu/news/2015-11-05/vitamin-c-kills-colorectal-cancer
Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues http://www.pnas.org/content/102/38/13604.short
Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC50 values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC50 of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H2O2 formation. Cell death from H2O2 added to cells was identical to that found when H2O2 was generated by ascorbate treatment. H2O2 generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H2O2, ascorbate addition to blood generated no detectable H2O2 and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial.
Oxalic acid excretion after intravenous ascorbic acid administration http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482487/
In our study, ascorbic acid was rapidly administered shortly after the infusate was prepared, whereas parenteral nutrition solutions are commonly infused over 12 to 24 hours, during which time considerable ascorbic acid degradation is known to occur. The present data are important because they indicate a remarkable lack of severe hyperoxaluria after massive intravenous doses of ascorbic acid in people with normal renal function.
Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics.
Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs.
This type of metabolic Achilles’ heel will allow us and others to more effectively “starve” the CSC population.
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