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FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, November 11, 2021

Summary of Recent Research with Three Nutrients in the War Against Cancer

by Michael Passwater

OMNS (Nov. 11, 2021) We have much to learn about preventing and treating cancer. Each disease in the cohort of cancers is potentially a different disease related to the specific genetic mutations that drive it. In the interest of promoting further efforts to improve our understanding of these complex diseases, here is an update on research involving three essential nutrients: vitamin C, selenium (selenite and methyl selenocysteine), and vitamin E (delta tocotrienol). Although much progress has been made in the fight against some types of cancer, many types still remain literally a death sentence. Each year, more than 1.3 million people are diagnosed with one of the ten most deadly types of cancer in the United States and over 400,000 people die from these dreaded diseases.

2021 Estimated Cancer Deaths and New Cases in the United States [1]

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Ascorbic Acid (Vitamin C)

By definition, a vitamin is essential for life, and vitamin C (ascorbic acid) is no exception. The health benefits of vitamin C are so extensive that it would be an important tool in the battle against cancer even without its powerful anti-tumor effect. Vitamin C is important for many aspects of immune and endothelial health; synthesis of catecholamines, carnitine, neuropeptides, neurotransmitters, collagen, and elastin; breakdown of L-tyrosine and hypoxic inducible factor 1-alpha (HIF-1a); epigenomic regulation; somatic stem cell reprogramming; and redox regulation including scavenging damaging free radicals, breaking chains of lipid peroxidation, and recycling other antioxidants. [2-8]

In 1976, Cameron and Pauling reported longer survival in terminal cancer patients given vitamin C. [9] Was this from improvement to the patients' constitution, was there an anti-tumor effect, or both? We now know that high doses of vitamin C can have a prooxidant effect, especially in combination with iron, which can selectively kill tumor cells containing less catalase than healthy human cells. [10, 11] The catalase enzyme is necessary for nearly all cells to remove hydrogen peroxide that can cause free radicals and damage the cell's biomolecules, including proteins and DNA. And vitamin C can also disrupt the "Warburg Effect" in tumor cells. [12,13,14] The Warburg Effect is the tendency of tumor cells to switch from using mitochondrial oxidative phosphorylation to aerobic glycolysis for the production of cellular energy (ATP). While greatly reducing the efficiency of energy production (2 ATP molecules generated per glucose molecule vs. 36 ATP molecules generated per glucose molecule), aerobic glycolysis enhances the ability of the cell to proliferate. Efficiency is only important when resources are scarce. In a glucose rich environment, 2 ATP molecules per glucose will work just fine, and allows more of the glucose, along with the amino acid glutamine, to provide the structures necessary to make additional tumor cells. This primitive, yet streamlined, tumor metabolism allows abundantly available glucose and glutamine to supply the biochemical needs of cell growth and division. Many tumor cells over-express glucose transporters, particularly GLUT1 to increase intake of glucose. Ascorbic acid, and especially oxidized ascorbic acid (dehydroascorbic acid) is similar in molecular shape to glucose, and can enter cells through these membrane transport channels. Not only does this disrupt the supply of glucose to the tumor cell, it also allows increased vitamin C concentrations within the cell where it can cause epigenetic effects including increasing TET enzyme activity, re-expression of tumor suppressor genes, or cause cell death through metabolic disruption. Depletion of intracellular glutathione leads to inactivation of glyceraldehyde 3-phosphate dehydrogenase and inhibition of glycolysis. In the setting of high vitamin C concentrations, the reliance of some tumor cells on aerobic glycolysis becomes their "Achilles' heel". [15]

In recent years, cell culture studies and human clinical trials have confirmed that tumor cells with KRAS and BRAF mutations can be selectively killed by appropriate doses of vitamin C. [16] KRAS and BRAF mutations are common in solid tumors, especially pancreatic, colon, and lung cancers. Synergistic effects have been seen by combining vitamin C with some chemotherapy drugs, radiation treatment, or in combination with a fasting-mimicking diet. [17-23] Mark Levine, Channing Paller, Tami Tamashiro, Thomas Luechtefeld and Amy Gravell recently reviewed 53 cancer clinical trials involving IV and/or oral vitamin C. [15] These trials give a clear signal of safety when patients with glucose 6 phosphate dehydrogenase (G6PD) deficiency are excluded from high dose IVC administration. Most studies were small, and involved a wide variety of late stage cancers. Nonetheless, encouraging signals were seen, including a few patients surviving years later eventually dying of causes other than cancer. Studies involving pancreatic ductal adenocarcinoma (PDAC) show a median survival following diagnosis of 3.5 months untreated, 6.7 months when treated with gemcitabine, 8.5 - 13 months when treated with gemcitabine and nab-paclitaxel, and 15.1 months when IVC with or without gemcitabine was used. [17,24] It is likely that with refinement of dosing and route of administration, earlier intervention, and improved knowledge of which tumors are most susceptible to high dose vitamin C therapy, more consistent positive results will be seen.

Three promising active clinical trials:

A Phase II Trial of Pharmacological Ascorbate, Gemcitabine, and Nab-Paclitaxel for Metastatic Pancreatic Cancer (PACMAN 2.1; University of Iowa Holden Comprehensive Cancer Center) [25]

A Phase II Study of High Dose Vitamin C Intravenous Infusion in Patients with Resectable or Metastatic Solid Tumor Malignancies (Weill Cornell Medicine, NYC) [26]

To download an informative description of "IV Vitamin C for Cancer Care", please click https://riordanclinic.org/wp-content/uploads/2017/09/IVChandout.pdf.
(Riordan Clinic, Kansas, >250,000 IVC treatments provided) [27]

Selenium

Selenium is a micronutrient essential for human health. There are 25 human selenoproteins known to be involved in numerous functions throughout the body, including brain, blood vessel, heart, and immune system health. These proteins perform diverse functions including antioxidant and redox recycling, gene "proof-reading", vitamin D metabolism, and hemostasis. Like vitamin C, even if there were no direct tumor effect of selenium, it would be an important tool in the battle for wellness and against cancer. [28-31]

HLA-E is a "camouflage protein" expressed by some tumors to hide from the immune system. The protein fools the immune system into thinking the tumor cell is a normal cell. A decade ago, selenite was shown to reduce - nearly eliminate - HLA-E expression on tumor cells. The tumor cells then became susceptible to destruction by Natural Killer cells (immune cells which clear unhealthy cells from the body). [32] A recent study of 243 PDAC patients showed that higher HLA-E and HLA-G (a similar protein) expression was associated with shorter survival. [33] In addition to optimizing tissue health throughout the body, the reduction of camouflage membrane proteins HLA-E and HLA-G by selenite may be a useful tool in the battle against cancer. Of note, selenomethionine (SeMet) had no effect on tumor cell HLA-E expression. Selenomethionine was the form of selenium used in the SELECT trial which did not show a benefit of selenium against prostate cancer prevention. In addition to the unfortunate choice of selenium supplement, the trial had other flaws, including a lack of difference in selenium levels between the control and test groups. Methyl selenocysteine (MSC) was the form of selenium used in the Nutritional Prevention of Cancer (NPC) trial which showed benefit. MSC is also the dominant form of selenium in broccoli, cabbage, onions and garlic. In 2014, MSC was shown to protect against the toxicity of four chemotherapy agents (cyclophosphamide, cisplatin, oxalplatin, and irinotecan), and enhance antitumor activity. [34]

More recently, a phase I study at Stanford using selenite and radiation therapy in humans validated the further study of selenite against cancer. [35] Additionally, in vitro and in vivo (mice) studies at the University of Grenada showed a strong antitumor effect of selenite against pancreatic cancer, alone and in combination with gemcitabine. [36]

Delta Tocotrienol

Vitamin E is an essential nutrient for humans. Vitamin E is a lipid soluble antioxidant. There are 8 different molecules in the vitamin E family pertinent to humans. It comprises 4 tocopherols (alpha, beta, gamma, delta), and 4 tocotreinols (alpha, beta, gamma, delta). Tocotreinols are smaller than tocopherols and are unsaturated. Tocotrienols have a half-life of approximately 4 hours while tocopherols have a half-life of 20 hours. Delta tocotrienol (VEDT = Vitamin E Delta Tocotrienol) is the smallest member of the vitamin E family, as it has the shortest "tail". Its small size allows delta tocotrienol greater mobility within lipid layers of cell membranes.

Studies have shown that tocotreinols inhibit Nuclear factor kappa B (NF-kB) activity and human pancreatic cancer cell survival, with VEDT having the strongest effect. [37] NF-kB is involved in immune and inflammatory responses, and in the regulation of cellular gene expression, proliferation, differentiation, and survival. VEDT has also been shown to enhance gemcitabine activity in pancreatic cancer cells. [38-40] Furthermore, VEDT has been shown to inhibit PDAC stem-like cells. VEDT significantly inhibited growth and metastases of these cells, including inhibiting the growth and metastasis of gemcitabine resistant PDAC stem-cell-like cells. [41] A phase I human clinical trial at Moffitt Cancer Center in Tampa, Florida showed 200 to 1600 mg VEDT taken orally daily for 2 weeks was well tolerated and significantly induced apoptosis (cell death) in pancreatic ductal cancer cells. [42] An anti-tumor effect, as well as a reduction in side effects from chemotherapy, has also been shown in the setting of other solid tumors. [43-56]

Note that to prevent the larger tocopherols from blocking absorption of the smaller tocotreinols, it is best to avoid taking tocopherols at the same time as tocotrienols. [57-63] Twice daily dosing of tocotrienols have been shown to produce a steady state after three days.

Summary

The redox synergy of vitamin C, vitamin E, and selenium-containing glutathione peroxidases has been explored since the 1960s and 1970s. Studies focusing on single nutrient interventions, with and without chemotherapy and radiation, have suggested benefit in humans, with increasingly specific mechanistic and treatment details discovered each decade. Along the way, a reassuring safety profile of nutrient interventions with and without traditional chemotherapy and radiation interventions has been established. Further studies to better define the most effective match of treatment for each tumor type, along with the best route, dose, and combination of treatments are important next steps to improve the reliability and effectiveness of preventing and treating the many types of cancer. Combining nutrients known to be synergistic together, while limiting glucose and glutamine central to the metabolism of many tumor cells, may optimize the effectiveness of treatment strategies.

With nutrient therapy - orthomolecular medicine - one does not need to choose between attacking the tumor and strengthening the host. The treatments often impact both simultaneously.

Foundational Support

  • NAD deficiency is associated with greater risk for mutagenesis with cancer and this is likely best avoided using daily niacin, e.g. start with 3x25-100mg/d to adapt to the flush, and then slowly work up to 3x500-1,000mg/d. [64] You can start by purchasing 100 mg tablets and break them into halves or quarters at first.
  • For cancer patients, chemotherapy commonly causes NAD deficiency, which is best rescued with niacinamide; e.g. 3x500mg/d. [64]
  • Dietary relevance, glutamine restriction with niacinamide; glucose restriction and ketogenic diet is recommended. [64]
  • Vitamin D3 to maintain plasma vitamin D > 40 ng/ml. Test a dose of 125 mcg/d (5000 IU) D3 with 100 mcg/d K2 for 4 months before getting a blood test for vitamin D.
  • 100 - 200 mcg/d selenium as methyl-selenocysteine or selenium yeast
  • 300 mg/d alpha lipoic acid
  • 1-2 g vitamin C with each meal
  • Exercise
  • Cultivate a cheerful heart [65]

Advanced Support

  • Vitamin C in divided doses throughout the day to bowl tolerance; consider mixtures of lipid- and water-soluble forms
  • IVC if G6PD levels are adequate and IVC is available from a licensed medical provider [66]
  • Sodium selenite if available from a licensed medical provider
  • Delta tocotrienol 300 - 1600 mg/d [42]

(Michael Passwater is certified by the American Society for Clinical Pathology as a Medical Technologist, a specialist in Immunohematology, and a diplomate in Laboratory Management. He has worked in clinical laboratories for 28 years, and has his degree in Medical Technology from the University of Delaware.)


References & Further Reading

1. National Cancer Institute. Common Cancer Types. https://www.cancer.gov/types/common-cancers

2. Oudemans-van Straaten HM, Spoelstra-de Man AME, de Waard MC. (2014) Vitamin C revisited. Critical Care 18:460-473. https://pubmed.ncbi.nlm.nih.gov/25185110

3. Manning J, Mitchell B, Appaduras DA, May JM, et al. (2013) Vitamin C Promotes Maturation of T-Cells. Antioxid Redox Signal. 19:2054-2067. https://pubmed.ncbi.nlm.nih.gov/23249337

4. Ladumer A, Schmitt CA, Schachner D, et al. (2012) Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status. Free Radic Biol Med. 2012 May 15; 52:2082-2090. https://pubmed.ncbi.nlm.nih.gov/22542797

5. May JM, Qu ZC. (2010) Ascorbic Acid Prevents Increased Endothelial Permeability Caused by Oxidized Low Density Lipoprotein. Free Radical Res. 44:1359-1368. https://pubmed.ncbi.nlm.nih.gov/20815791

6. Deicher R, Ziai F, Begknayer C, et al. (2005) Low Total Vitamin C Plasma Level Is a Risk Factor for Cardiovascular Morbidity and Mortality in Hemodialysis Patients. J Am Soc Nephrol. 16:1811-1818. https://pubmed.ncbi.nlm.nih.gov/15814831

7. Heller R, Munscher-Paulig F, Grabner R, Till V. (1999) L-Ascorbic Acid Potentiates Nitric Oxide Synthesis in Endothelial Cells. J Biol Chem, 274:8254-8260. https://pubmed.ncbi.nlm.nih.gov/10075731

8. Leibovitz B, Siegel BV. (1978) Ascorbic acid, neutrophil function, and the immune response. Int J Vitam Nutr Res. 48:159-164. https://pubmed.ncbi.nlm.nih.gov/357320

9. Cameron E, Pauling L. (1976) Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA. 73: 3685-3689. https://pubmed.ncbi.nlm.nih.gov/1068480

10. Schoenfeld JD, Sibenaller ZA Mapuskar KA, et al (2017) O2- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell 31: 487-500. https://pubmed.ncbi.nlm.nih.gov/28366679

11. O'Leary BR, Alexander MS, Du J, et al (2020) Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism. Sci Rep 10:17649 https://pubmed.ncbi.nlm.nih.gov/33077776.

12. Aguilera O, Muñoz-Sagastibelza M, Torrejón E, et al. (2016) Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer. Oncotarget, 7:47954-47965. https://pubmed.ncbi.nlm.nih.gov/27323830

13. Suzuki T, Kishikawa T, Sato T, et al. (2021) Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells. Cancer Gene Ther. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/33833413

14. Gonzalez MJ, Seyfried T; Nicolson GL et al. (2018) Mitochondrial Correction: A New Therapeutic Paradigm for Cancer and Degenerative Diseases. J Orthomolecular Med 33: 4. https://riordanclinic.org/journal-article-archive/mitochondrial-correction-a-new-therapeutic-paradigm-for-cancer-and-degenerative-diseases

15. Chen Q, Vissers MCM (2020) Cancer and Vitamin C. CRC Press. ISBN-13: 978-0367858049

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17. Polireddy K, Dong R, Reed G, et al. (2017) High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study. Sci Rep 7: 17188 https://pubmed.ncbi.nlm.nih.gov/29215048

18. Alexander MS, Wilkes JG, Schroeder SR, Buettner GR. (2018) Pharmacologic ascorbate reduces radiation-induced normal tissue toxicity and enhances tumor radiosensitization in pancreatic cancer. Cancer Res. 78:6838-6851. https://pubmed.ncbi.nlm.nih.gov/30254147.

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20. Welsh JL, Wagner BA, van't Erve TJ, et al. (2013) Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother. Pharmacol. 71:765-775. https://pubmed.ncbi.nlm.nih.gov/23381814

21. Monti DA, Mitchell E, Bazzan AJ, et al. (2012) Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS ONE 7(1):e29794. https://pubmed.ncbi.nlm.nih.gov/22272248

22. Mikirova N, Casciari J, Hunninghake R. (2019) Continuous Intravenous Vitamin C in the Cancer Treatment: Reevaluation of a Phase I Clinical Study. Functional Foods in Health and Disease. https://riordanclinic.org/journal-article-archive/continuous-intravenous-vitamin-c-in-the-cancer-treatment-reevaluation-of-a-phase-i-clinical-study

23. Di Tano M, Raucci F, Vernieri C, et al. (2020) Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nat Comm 11:2332 https://pubmed.ncbi.nlm.nih.gov/32393788

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25. Cullen JJ (2021) A Phase II Trial of Pharmacological Ascorbate, Gemcitabine, and Nab-Paclitaxel for Metastatic Pancreatic Cancer (PACMAN 2.1) https://clinicaltrials.gov/ct2/show/NCT02905578

26. Shah MA, Khan U. (2021) A Phase II Study of High Dose Vitamin C Intravenous Infusion in Patients with Resectable or Metastatic Solid Tumor Malignancies. https://jcto.weill.cornell.edu/open_clinical_trials/a-phase-ii-study-of-high-dose-vitamin-c-intravenous-infusion-in-patients-with-resectable-or-metastatic-solid-tumor-malignancies

27. Riordan Clinic (2021) High Dose IV Vitamin C (IVC) https://riordanclinic.org/what-we-do/high-dose-iv-vitamin-c

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Editorial Review Board:

Albert G. B. Amoa, MB.Ch.B, Ph.D. (Ghana)
Seth Ayettey, M.B., Ch.B., Ph.D. (Ghana)
Ilyès Baghli, M.D. (Algeria)
Ian Brighthope, MBBS, FACNEM (Australia)
Gilbert Henri Crussol, D.M.D. (Spain)
Carolyn Dean, M.D., N.D. (USA)
Ian Dettman, Ph.D. (Australia)
Damien Downing, M.B.B.S., M.R.S.B. (United Kingdom)
Susan R. Downs, M.D., M.P.H. (USA)
Ron Ehrlich, B.D.S. (Australia)
Hugo Galindo, M.D. (Colombia)
Martin P. Gallagher, M.D., D.C. (USA)
Michael J. Gonzalez, N.M.D., D.Sc., Ph.D. (Puerto Rico)
William B. Grant, Ph.D. (USA)
Claus Hancke, MD, FACAM (Denmark)
Tonya S. Heyman, M.D. (USA)
Suzanne Humphries, M.D. (USA)
Ron Hunninghake, M.D. (USA)
Bo H. Jonsson, M.D., Ph.D. (Sweden)
Dwight Kalita, Ph.D. (USA)
Felix I. D. Konotey-Ahulu, MD, FRCP, DTMH (Ghana)
Jeffrey J. Kotulski, D.O. (USA)
Peter H. Lauda, M.D. (Austria)
Alan Lien, Ph.D. (Taiwan)
Homer Lim, M.D. (Philippines)
Stuart Lindsey, Pharm.D. (USA)
Victor A. Marcial-Vega, M.D. (Puerto Rico)
Charles C. Mary, Jr., M.D. (USA)
Mignonne Mary, M.D. (USA)
Jun Matsuyama, M.D., Ph.D. (Japan)
Joseph Mercola, D.O. (USA)
Jorge R. Miranda-Massari, Pharm.D. (Puerto Rico)
Karin Munsterhjelm-Ahumada, M.D. (Finland)
Tahar Naili, M.D. (Algeria)
W. Todd Penberthy, Ph.D. (USA)
Zhiyong Peng, M.D. (China)
Isabella Akyinbah Quakyi, Ph.D. (Ghana)
Selvam Rengasamy, MBBS, FRCOG (Malaysia)
Jeffrey A. Ruterbusch, D.O. (USA)
Gert E. Schuitemaker, Ph.D. (Netherlands)
T.E. Gabriel Stewart, M.B.B.CH. (Ireland)
Thomas L. Taxman, M.D. (USA)
Jagan Nathan Vamanan, M.D. (India)
Garry Vickar, M.D. (USA)
Ken Walker, M.D. (Canada)
Anne Zauderer, D.C. (USA)

Andrew W. Saul, Ph.D. (USA), Editor-In-Chief
Associate Editor: Robert G. Smith, Ph.D. (USA)
Editor, Japanese Edition: Atsuo Yanagisawa, M.D., Ph.D. (Japan)
Editor, Chinese Edition: Richard Cheng, M.D., Ph.D. (USA)
Editor, French Edition: Vladimir Arianoff, M.D. (Belgium)
Editor, Norwegian Edition: Dag Viljen Poleszynski, Ph.D. (Norway)
Editor, Arabic Edition: Moustafa Kamel, R.Ph, P.G.C.M (Egypt)
Editor, Korean Edition: Hyoungjoo Shin, M.D. (South Korea)
Editor, Spanish Edition: Sonia Rita Rial, PhD (Argentina)
Contributing Editor: Thomas E. Levy, M.D., J.D. (USA)
Assistant Editor: Helen Saul Case, M.S. (USA)
Technology Editor: Michael S. Stewart, B.Sc.C.S. (USA)
Associate Technology Editor: Robert C. Kennedy, M.S. (USA)
Legal Consultant: Jason M. Saul, JD (USA)

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