vitamin C IV for Cancer

1)  Mastrangelo, Domenico, et al. “Cytotoxic effects of high concentrations of sodium ascorbate on human myeloid cell lines.” Annals of hematology 94.11 (2015): 1807-1816.

The effect of high doses of intravenous (sodium) ascorbate (ASC) in the treatment of cancer has been controversial although there is growing evidence that ASC in high (pharmacologic) concentrations induces dose-dependent pro-apoptotic death of tumor cells, in vitro. Very few data are available on the role of ASC in the treatment of acute myeloid leukemia (AML). Ascorbate behaves as an antioxidant at low (physiologic), and as pro-oxidant at pharmacologic, concentrations, and this may account for the differences reported in different experimental settings, when human myeloid cell lines, such as HL60, were treated with ASC. Considering the myeloid origin of HL60 cells, and previous literature reports showing that some cell lines belonging to the myeloid lineage could be sensitive to the pro-apoptotic effects of high concentrations of ASC, we investigated in more details the effects of high doses (0.5 to 7 mM) of ASC in vitro, on a variety of human myeloid cell lines including the following: HL60, U937, NB4, NB4-R4 (retinoic acid [RA]-resistant), NB4/AsR (ATO-resistant) acute promyelocytic leukemia (APL)-derived cell lines, and K562 as well as on normal CD34+ progenitors derived from human cord blood. Our results indicate that all analyzed cell lines including all-trans retinoic acid (ATRA)- and arsenic trioxide (ATO)-resistant ones are highly sensitive to the cytotoxic, pro-oxidant effects of high doses of ASC, with an average 50 % lethal concentration (LC50) of 3 mM, depending on cell type, ASC concentration, and time of exposure. Conversely, high doses of ASC neitherdid exert significant cytotoxic effects nor impaired the differentiation potential in cord blood (CB) CD34+ normal cells. Since plasma ASC concentrations within the millimolar (mM) range can be easily and safely reached by intravenous administration, we conclude that phase I/II clinical trials using high doses of ASC should be designed for patients with advanced/refractory AML and APL.
free pdf

2) Goodman, Annekathryn. “Vitamin C and cancer.” AIMS Medical Science 3.1 (2016): 41-51. Vitamin C and cancer Goodman AIMS Medical Science 2016
Venturelli et al have suggested combining hyperbaric oxygen or O2 sensitizers with the use of vitamin C

Vitamin C AND D3 Augment Effects of ARTEMISININ

3) Gerhardt, Thomas, et al. “Effects of antioxidants and pro-oxidants on cytotoxicity of dihydroartemisinin to Molt-4 human leukemia cells.” Anticancer research 35.4 (2015): 1867-1871. Antioxidants and Pro oxidants cytotoxicity of dihydroartemisinin to leukemia cells Gerhardt Anticancer Res 2015

Compared to control, ascorbate and H2O2 both caused a significant decrease in cell count both at 24-h (p<0.05 and p<0.0001 for ascorbate and H2O2, respectively) and 48-h (p<0.0001 for both ascorbate and H2O2) time points.  It may be possible to improve therapeutic outcomes by compounding  the oxidizing effect of artemisinin and certain supplements, pushing cancer cells toward oxidative overload (14).  We hypothesize that ascorbate acts more like a pro-oxidant in cancer cells due to their higher cytoplasmic iron levels.

regression of Pulmonary Mets

4) Seo, Min-Seok, Ja-Kyung Kim, and Jae-Yong Shim. “High-dose vitamin C promotes regression of multiple pulmonary metastases originating from hepatocellular carcinoma.” Yonsei medical journal 56.5 (2015): 1449-1452.

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.

5) Mastrangelo, D. “The Cure from Nature: The Extraordinary Anticancer Properties of Ascorbate (Vitamin C).” J Integr Oncol 5 (2016): 157.

ascorbate seems to behave differently not just according to its dose, but rather according to the target cell, being an antioxidant for normal cells, and pro- oxidant for cancer cells.
Almost a hundred years ago, Paul Erlich, the founder of modern chemotherapy, who received the Nobel Prize for Physiology and Medicine, hypothesized the creation of the “magic bullet” for use in the fight against human disease, thus inspiring generations of scientists to devise new powerful anticancer agents: today we know that the “magic bullet” is here; ascorbate, in vitro is extremely effective and selective, as we have demonstrated in leukemic cells lines and their normal counterpart [36] … to the clinical oncologists the endeavor and responsibility to translate these wonderful data in a clinical (revolutionary) reality!.

Ron Hunninghake

6) http://orthomolecular.org/library/ivccancerpt.shtml
INTRAVENOUS VITAMIN C and CANCER  Ron Hunninghake

Integrative Cancer Therapies, titled “Orthomolecular Oncology Review: Ascorbic Acid and Cancer 25 Years Later.” RECNAC data has shown that vitamin C is toxic to tumor cells without sacrificing the performance of chemotherapy.

Garry Beuttner Figure 1
Cancer Cells have less Catalase for degradation of H202

7) Doskey, Claire M., et al. “Tumor cells have decreased ability to metabolize H 2 O 2: Implications for pharmacological ascorbate in cancer therapy.” Redox Biology 10 (2016): 274-284.

We have previously shown that the extracellular flux of H₂O₂ generated by the P-AscH^– in the medium will increase the intracellular steady-state levels of H₂O_2.  Kinetic models indicate that catalase is the major antioxidant enzyme involved in the removal of H₂O₂ at concentrations greater than 10 µM, leading us to investigate the catalase activity in the tumor cell lines

7a)  Olney KE, Du J, van ’t Erve TJ, et al. INHIBITORS OF HYDROPEROXIDE METABOLISM ENHANCE ASCORBATE-INDUCED CYTOTOXICITY. Free radical research. 2013;47(3):154-163.

IV Vitamin C for Relapsed Refractory B cell lymphoma

8) https://www.ncbi.nlm.nih.gov/pubmed/25248425
KAWADA, Hiroshi, et al. “Phase I Clinical Trial of Intravenous L-ascorbic Acid Following Salvage Chemotherapy for Relapsed B-cell non-Hodgkin’s Lymphoma.” The Tokai journal of experimental and clinical medicine 39.3 (2014): 111-115.
PURPOSE:To determine the safety and the appropriate dose of intravenous l-ascorbic acid (AA) in conjunction with chemotherapy for patients with relapsed lymphoma.
PATIENTS AND METHODS:Patients with relapsed CD20-positive B-cell non-Hodgkin’s lymphoma, who were going to receive the CHASER regimen as salvage therapy, were enrolled and treated with escalating doses of AA administered by drip infusion after the 2nd course of the CHASER regimen. The target plasma concentration immediately after AA administration was >15 mM (264 mg/dl).
RESULTS: A serum AA concentration of  >15 mM was achieved in 3 sequentially registered patients, all of whom had received a 75 g whole body dose. No obvious adverse drug reaction was observed in the patients. The trial was therefore successfully completed.
CONCLUSION:Intravenous AA at a whole body dose of 75 g appears to be safe and sufficient to achieve an effective serum concentration. A phase II trial to evaluate the efficacy of intravenous AA in relapsed/refractory lymphoma patients will now be initiated.

9) Levine, Mark, Sebastian J. Padayatty, and Michael Graham Espey. “Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries.” Advances in Nutrition: An International Review Journal 2.2 (2011): 78-88.

10)  Frömberg, Anja, et al. “Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs.” Cancer chemotherapy and pharmacology 67.5 (2011): 1157-1166.

11)  Du, Juan, et al. “Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer.” Clinical Cancer Research 16.2 (2010): 509-520.

12) Verrax, Julien, and Pedro Buc Calderon. “Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects.” Free Radical Biology and Medicine 47.1 (2009): 32-40.  Pharmacologic concentrations ascorbate achieved parenteral administration antitumoral effects Verra Julien Free Radical Biology Med 2009

Riordan Clinic Research Institute  February 2013

13) The Riordan IVC Protocol for Adjunctive Cancer Care
Intravenous Ascorbate as a Chemotherapeutic and Biological Response Modifying Agent Riordan IVC Protocol Adjunctive Cancer Care IV Vitamin C Ascorbate Feb 2013

IV site irritation may occur at the infusion site when given in a vein and not a port. This can be caused by an infusion rate exceeding 1.0 gram/minute. The protocol suggests adding magnesium to reduce the incidence of vein irritation and spasm.

Eating before the IVC infusion is recommended to help reduce blood sugar fluctuations.

IVC should only be given by slow intravenous drip at a rate of 0.5 grams per minute. (Rates up to 1.0 gram/minute are generally tolerable, but close observation is warranted. Patients can develop nausea, shakes, and chills.

We presently use a sodium ascorbate solution, MEGA-C-PLUS®, 500 mg/mL, pH range 5.5-7.0 from Merit Pharmaceuticals, Los Angeles, CA, 90065.

We advise patients to orally supplement with at least 4 grams of vitamin C daily, especially on the days when no infusions are given, to help prevent a possible vitamin C “rebound effect.” Oral alpha lipoic acid is also recommended on a case by case basis.

Vitamin C as anti-viral agent

14) MIkirova, Nina, and Ronald Hunninghake. “Effect of high dose vitamin C on Epstein-Barr viral infection.” Medical Science Monitor 20 (2014): 725-732.  High dose vitamin C Epstein-Barr viral infection MIkirova Nina Ronald Hunninghake Medical Science Monitor 2014

Background: Many natural compounds were tested for the ability to suppress viral replication. The present manuscript details an analysis of high dose vitamin C therapy on patients with EBV infection.
Material and Methods: The data were obtained from the patient history database at the Riordan Clinic. Among people in our database who were treated with intravenous vitamin C (7.5 g to 50 g infusions) between 1997 and 2006, 178 patients showed elevated levels of EBV EA IgG (range 25 to 211 AU) and 40 showed elevated levels of EBV VCA IgM (range 25 to 140 AU). Most of these patients had a diagnosis of chronic fatigue syndrome, with the rest being diagnosed as having mononucleosis, fatigue, or EBV infection.
Results: Our data provide evidence that high dose intravenous vitamin C therapy has a positive effect on disease duration and reduction of viral antibody levels.
Plasma levels of ascorbic acid and vitamin D were correlated with levels of antibodies to EBV. We found an inverse correlation between EBV VCA IgM and vitamin C in plasma in patients with mononucleosis and CFS meaning that patients with high levels of vitamin C tended to have lower levels of antigens in the acute state of disease.
In addition, a relation was found between vitamin D levels and EBV EA IgG with lower levels of EBV early antigen IgG for higher levels of vitamin D.
Conclusions: The clinical study of ascorbic acid and EBV infection showed the reduction in EBV EA IgG and EBV VCA IgM antibody levels over time during IVC therapy that is consistent with observations from the literature that millimolar levels of ascorbate hinder viral infection and replication in vitro.

Chen 2005

15)  Chen, Qi, et al. “Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.” Proceedings of the national academy of sciences of the United States of America 102.38 (2005): 13604-13609.
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.

see fig 4 good illustration of H2O2 formation

Chen – glioblastoma xenografts

16) Chen, Qi, et al. “Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.” Proceedings of the National Academy of Sciences 105.32 (2008): 11105-11109.
Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.

17)  Chen, Qi, et al. “Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo.” Proceedings of the National Academy of Sciences 104.21 (2007): 8749-8754.

Hugh D. Riordan, Stephen M. Hewitt, Arie Katz, L. John Hoffer, Mark Levine

18) Padayatty, Sebastian J., et al. “Intravenously administered vitamin C as cancer therapy: three cases.” Canadian Medical Association Journal 174.7 (2006): 937-942.

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.

John Hoffer MD – Lymphoma Remission with Vit C IV

19) The Journal of Orthomolecular Medicine Vol. 15, 4th Quarter 2000
Vitamin C: A Case History of an Alternative Cancer Therapy
John Hoffer, M.D., Ph.D.

Also striking was the report, in a subsequent paper by Cameron, Campbell and Jack, of two vitamin C-induced complete remissions in the same patient of a stage IVB non-Hodgkins lymphoma.12 The patient was a 42 year-old truck driver who developed fever and constitutional symptoms in 1973, and was found to have a right pulmonary infiltrate. Two months later the infiltrate had evolved into mediastinal and hilar enlargement, and a pleural effusion was present. The clinical diagnosis of lung cancer was made and no treatment offered. However, when the patient then developed hepatosplenomegaly and extensive peripheral lymphadenopathy, a lymph node biopsy was carried out and the diagnosis of non-Hodgkin’s lymphoma was made. The accuracy of this diagnosis was later confirmed by expert pathologists.5,10 Although the plan at that time was for radiotherapy and cytotoxic chemotherapy, an administrative delay in obtaining the patient’s transfer to a referral center and his poor clinical condition motivated his physicians to administer intravenous vitamin C. The response was so strikingly favorable that all indications for standard lymphoma therapy promptly disappeared. Within a few days the patient experienced a return of well-being associated with complete regression of lymphadenopathy and hepatosplenomegaly. The pleural effusion resolved and the chest x-ray became normal. After three months vitamin C therapy was tapered and stopped. Four weeks after stopping vitamin C, the patient’s constitutional symptoms returned and a repeat chest x-ray again showed right hilar enlargement and a pleural effusion. The patient was started on oral ascorbic acid, but it was ineffective in preventing further clinical deterioration, so he was admitted to hospital for an intravenous ascorbic acid infusion (20 g/day for 14 days) followed by oral ascorbic acid. A slow but sustained clinical improvement resulted. As of 1979, the patient, still on vitamin C, remained in complete remission.5

20) Hoffer, L. John, et al. “High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.” PloS one 10.4 (2015): e0120228.

Mercola

21) Vitamin C: The Supplement Almost Everyone Should Take When They Are Sick  November 20, 2010  Mercola

22)  Vitamin C May Be a Potent Adjunct to Cancer Treatment March 06, 2017  Mercola

23)  Why high-dose vitamin C kills cancer cells, Low levels of catalase enzyme make cancer cells vulnerable to ascorbate
By: Jennifer Brown  2017.01.10

Ron Hunninghake, MD

24) https://riordanclinic.org/our-locations/
Ron Hunninghake, MD  Chief Medical Officer
Wichita Kansas – Main Campus
316-682-3100 | 3100 N Hillside Ave • Wichita, KS 67219
MORE ABOUT THIS LOCATION
Hays Kansas
785-628-3215 | 1010 E 17th St.• Hays, KS 67601
MORE ABOUT THIS LOCATION
Kansas City
913.745.4757 | 21620 Midland Drive Suite B, Shawnee, KS 66218

25) How Vitamin C Fights Cancer by Ron Hunninghake (Transcript)

Vitamin C Synergy with Chemotherapy

26)  Kurbacher, Christian M., et al. “Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro.” Cancer letters 103.2 (1996): 183-189.

27)  Drisko, Jeanne A., Julia Chapman, and Verda J. Hunter. “The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer.” Journal of the American College of Nutrition 22.2 (2003): 118-123.

28) Ma, Yan, et al. “High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.” Science translational medicine 6.222 (2014): 222ra18-222ra18.  High dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer reduced toxicity chemotherapy Ma Yan Mark Levine Sci trans med 2014

Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.

Riordan Clinic Hugh D. Riordan

29) González, Michael J., et al. “Orthomolecular oncology review: ascorbic acid and cancer 25 years later.” Integrative cancer therapies 4.1 (2005): 32-44. Hugh D. Riordan   Orthomolecular oncology rev ascorbic acid cancer 25 years later González Michael Hugh D Riordan Int cancer ther 2005

“AA Ascorbic Acid (Vit C) is one of the safest and most valuable substances available to the physician for treating cancer.”

the combination of megadoses of IV ascorbate togetherwith oxygen, vitamin K, lipoic acid, coenzyme Q10,and small doses of copper may seem logical as part of anontoxic treatment protocol for cancer.To ascorbate’s advantage, tumor cells have an increased requirement for glucose.104To compensate for this increased need for glucose, tumor cells increase their quantity of glucose transporters.105  This action greatly enhances the entrance of either ascorbate or its oxidized form,

dehydroascorbate, into the cancer cell. This facilitates the action of ascorbate as a selective, nontoxic (to normal cells) chemotherapeutic agent.  Since AA and glucose have similar molecular structures, cellular intake of vitamin C is favored in malignant cells.

Lipoic acid (thioctic acid), an aqueous and lipid-soluble antioxidant that recycles vitamin C, decreased the dose of vitamin C required to kill 50% of tumor cells from 700 mg/dL to 120 mg/dL.

“AA Ascorbic Acid (Vit C) is one of the safest and most valuable substances available to the physician for treating cancer.”

31) http://ar.iiarjournals.org/content/29/3/809.long Ohno, Satoshi, et al. “High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer.” Anticancer research 29.3 (2009): 809-815.

32) http://www.pnas.org/content/105/32/11037.long
Frei, Balz, and Stephen Lawson. “Vitamin C and cancer revisited.” Proceedings of the National Academy of Sciences 105.32 (2008): 11037-11038.

Older literature

33) http://www.pnas.org/content/73/10/3685.full.pdf?
Cameron, Ewan, and Linus Pauling. “Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer.” Proceedings of the National Academy of Sciences 73.10 (1976): 3685-3689.

34) Cameron, Ewan, and Linus Pauling. “Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer.” Proceedings of the National Academy of Sciences 75.9 (1978): 4538-4542.

35) https://www.ncbi.nlm.nih.gov/pubmed/7609676
Riordan, N. H., et al. “Intravenous ascorbate as a tumor cytotoxic chemotherapeutic agent.” Medical hypotheses 44.3 (1995): 207-213.

36) http://www.doctoryourself.com/ckorea2008.html
High-Dose Vitamin C Therapy for Major Diseases (Seoul, Korea. September 25, 2008)  Andrew W. Saul                                                    Editor-in-Chief, Orthomolecular Medicine News Service; Assistant Editor, Journal of Orthomolecular Medicine.

37) Pollard, Harvey B., et al. “Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer.” in vivo 24.3 (2010): 249-255.
We report here that ascorbic acid treatment does lead to both the suppression of the primary tumor mass, and also to the reduction in the incidence of lung metastases. Additionally, we found that ascorbic acid treatment changes the quantitative relationship between primary tumor weight and the number of lung metastases from random to essentially linear. This is the first report of ascorbic acid effects on tumor biology in a syngeneic, immune-competent rodent system.

38)  Mayland, Catriona R., Michael I. Bennett, and Keith Allan. “Vitamin C deficiency in cancer patients.” Palliative medicine 19.1 (2005): 17-20.To assess the prevalence of vitamin C deficiency within a group of hospice patients. To assess the relationship between plasma vitamin C, dietary intake and subsequent survival.
METHODS:Patients with advanced cancer were recruited from a large hospice. Data were collected on demographic details, physical functioning and smoking history. An estimate was obtained of the number of weekly dietary portions consumed equivalent to 40 mg of vitamin C, the recommended daily intake. Plasma vitamin C was measured by a single blood sample. The study had local ethical approval.
RESULTS:Fifty patients were recruited (mean age 65.2 years, 28 female). Plasma vitamin C deficiency was found in 15 (30%). Dietary intake of vitamin C was correlated to plasma vitamin C (r=0.518, P<0.0001). Low dietary intake, low albumin, high platelet count, high CRP level and shorter survival were all significantly associated with low plasma vitamin C concentrations (<11 micromol/L). There was no correlation between plasma vitamin C, smoking history or physical functioning.
CONCLUSION:Vitamin C deficiency is common in patients with advanced cancer and the most important factors determining plasma levels are dietary intake and markers of the inflammatory response. Patients with low plasma concentrations of vitamin C have a shorter survival.

IV vit C synergy with vitamin K3

39) Verrax, Julien, et al. “Redox-active quinones and ascorbate: an innovative cancer therapy that exploits the vulnerability of cancer cells to oxidative stress.” Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 11.2 (2011): 213-221. Quinones and ascorbate exploits vulnerability cancer cells to oxidative stress Verrax Julien Anti Cancer 2011

40) Apatone   Vit C and Menadione (VK3)
Tareen, Basir, et al. “A 12 week, open label, phase I/IIa study using apatone for the treatment of prostate cancer patients who have failed standard therapy.” Int J Med Sci 5.2 (2008): 62-67.Tareen Basir Apatone for prostate cancer Ascorbate K3 Int J Med Sci 2008

When VC and VK3 were combined in a ratio of 100:1(Apatone) and administered to human tumor cell lines,including androgen independent prostate cancer cells(DU145), they exhibited a synergistic inhibition of cellgrowth and induced cell death by apoptosis at concentrations that were 10 to 50 times lower than for the individual vitamins

41) Ascorbate, vitamin K3 and hydroxytolans in the treatment of cancer
US 8680142 B2  Abstract  The combination of compounds of the hydroxytolan family with ascorbate plus naphthoquinone (Vitamin K3; VK3), or a quinone or semiquinone analogue of VK3, kill tumor cells, inhibit tumor growth and development, and treat cancer in subjects in need thereof.

42) Gilloteaux, Jacques, et al. “Synergistic antitumor cytotoxic actions of ascorbate and menadione on human prostate (DU145) cancer cells in vitro: nucleus and other injuries preceding cell death by autoschizis.” Ultrastructural pathology 38.2 (2014): 116-140.ascorbate and menadione on human prostate cancer death by autoschizis Gilloteaux Jacques Ultrastruct path 2014

42A) Lamson, Davis W., et al. “The vitamin C: vitamin K3 system-enhancers and inhibitors of the anticancer effect.” Altern Med Rev 15.4 (2010): 345-351.Vitamin C and K3 Anticancer Effect Lamson Davis Altern Med Rev 2010

43) Bonilla-Porras, Angelica R., Marlene Jimenez-Del-Rio, and Carlos Velez-Pardo. “Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism   .” Cancer cell international 11.1 (2011): 19.

44) Ma, Wei-Dong, et al. “Chimaphilin induces apoptosis in human breast cancer MCF-7 cells through a ROS-mediated mitochondrial pathway.” Food and Chemical Toxicology 70 (2014): 1-8.

IV Vitamin C targets Cancer stem cells

45) Bonuccelli G, De Francesco EM, de Boer R, Tanowitz HB, Lisanti MP. NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting “stemness.” Oncotarget. 2017;8(13):20667-20678. doi:10.18632/oncotarget.15400.

Increased Iron in Cancer Cells reacts with H202 from  Ascorbate to kill cells

46) Vitamin C puts the pedal to the metal Monica Venere
Increased iron in cancer cells drives selective sensitization of tumors to ascorbate treatment to prolong survival.

47) O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate,  Schoenfeld, Joshua D. et al. Cancer Cell Volume 31, Issue 4, p487–500.e8, 10 April 2017

High-dose ascorbate sensitizes NSCLC and GBM cells to radio-chemotherapy
•O2⋅− and H2O2 increase labile iron causing cancer cell-selective ascorbate toxicity
•Therapeutic levels of ascorbate are achievable and well tolerated in GBM and NSCLC
•Cancer cell oxidative metabolism can be targeted with ascorbate for cancer therapy

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

48) Toyokuni, Shinya, et al. “Iron and thiol redox signaling in cancer: an exquisite balance to escape ferroptosis.” Free Radical Biology and Medicine (2017).  Cancer cells are under persistent oxidative stress with a delicate balance between catalytic iron and thiols, thereby escaping ferroptosis. Thus, high-dose L-ascorbate and non-thermal plasma as well as glucose/glutamine deprivation may provide additional benefits as cancer therapies over preexisting therapeutics.

49) McCarty, Mark Frederick, and Francisco Contreras. “Increasing superoxide production and the labile iron pool in tumor cells may sensitize them to extracellular ascorbate.” Frontiers in oncology 4 (2014).

50) Mata, Ana Maria Oliveira Ferreira da, et al. “Ascorbic acid in the prevention and treatment of cancer.” Revista da Associação Médica Brasileira 62.7 (2016): 680-686. Ascorbic acid in the prevention and treatment of cancer Mata Revista da Associacao Medica Brasileira 2016

Ascorbate synergy with alpha lipoic acid  – Riordan Clinic

51) Casciari, J. J., Riordan et al. “Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours.” British journal of cancer 84.11 (2001): 1544. 88)  Cytotoxicity of ascorbate and alpha lipoic acid in vitro tumours Casciari Brit J Cancer 2001

52) Patented by  Riordan Clinic  –Treatment of cancer using lipoic acid in combination with ascorbic acid  US 6448287 B1

Lipoic acid and/or its water soluble salt is used to treat cancer, alone or in combination with ascorbic acid (vitamin C). Alone or in combination, it was shown to be effective on in vitro tumors and mouse tumors. The agents can be administered safely, and have been used effectively in case studies.

Electron Microscopy of Mitochondria in cancer cells

53) Xia, Jiliang, et al. “Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid.” EBioMedicine 18 (2017): 41-49.

High-dose chemotherapies to treat multiple myeloma (MM) can be life-threatening due to toxicities to normal cells and there is a need to target only tumor cells and/or lower standard drug dosage without losing efficacy. We show that pharmacologically-dosed ascorbic acid (PAA), in the presence of iron, leads to the formation of highly reactive oxygen species (ROS) resulting in cell death. PAA selectively kills CD138+ MM tumor cells derived from MM and smoldering MM (SMM) but not from monoclonal gammopathy undetermined significance (MGUS) patients. PAA alone or in combination with melphalan inhibits tumor formation in MM xenograft mice. This study shows PAA efficacy on primary cancer cells and cell lines in vitro and in vivo.

Hyperbaric 02 augments IV vitamin C

54)  Increasing the Effectiveness of Intravenous Vitamin C as an Anticancer Agent. Journal of Orthomolecular Medicine Volume 32, Number 1, 2017.  JOM Archives, Volume 30, Number 1, 2015
We propose the utilization of hyperbaric oxygen immediately after IV vitamin C therapy to increase its effectiveness as an anticancer agent, in order to increase the formation of hydrogen peroxide, and therefore enhance the anticancer effect of IV vitamin C.

55)  Research Links Oceanside Hyperbaric

56) Pharmacological Ascorbic Acid and Hyperbaric Oxygen Therapy Target Tumor Cell Metabolism via an Oxidative Stress Mechanism
Submitted on 08 Feb 2017
Janine M. DeBlasi, Nathan P. Ward, PhD, Angela M. Poff, PhD, Andrew P. Koutnik, BS, Christopher Q. Rogers, PhD, David M. Diamond, PhD, Dominic P. D’Agostino, PhD Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL
High-dose ascorbic acid (AA) is an anti-carcinogenic, minimally toxic, metabolic therapy that targets tumor cell metabolism via an oxidative stress (OxS) mechanism. At pharmacological levels (achieved i.v.), AA delivers H2O2 to tumorous tissue upon oxidation, initiating cell death. High-dose AA has shown significant anticancer effects in vitro, in vivo, and in small-scale human reports at concentrations nontoxic to normal cells, thus having great potential as an adjuvant to the standard of care. Hyperbaric oxygen therapy (HBOT) is another non-toxic, pro-oxidative, metabolic therapy that delivers 100% oxygen at elevated barometric pressure, elevating tissue pO2 and oxygenating hypoxic tumor cells, which, when coupled with high levels of reactive oxygen and nitrogen species present in cancer cells, can further augment OxS and lead to cell death. We hypothesized that AA would induce ROS-dependent OxS and that this would be further augmented with HBOT. This study’s aims were as follows (1) to examine the anticancer effect of AA in vitro, (2) to evaluate the mechanism of AA-induced OxS, (3) to determine if HBOT and AA are synergistic.
To characterize the anticancer effects of AA in vitro, we measured cell viability and proliferation following treatment with graded concentrations of AA in mouse brain tumor-derived VM-M3 cells. We found that AA mediates cell death in a concentration-dependent manner, and that concentrations great than or equal to 0.5mM AA significantly induced cell death compared to control. We also found that concentrations > 0.05mM AA inhibit cell proliferation compared to control and 0.01mM AA at 72 and 96 hours of growth. To investigate the role of OxS in AA-induced cytotoxicity, we measured VM-M3 cell viability in the presence of AA and antioxidant N-Acetylcysteine (NAC), and found that treatment with 0.5 and 5mM NAC attenuates the OxS-induced cytotoxic effect of AA. To determine if HBOT can enhance the therapeutic effect of AA, we measured VM-M3 cell viability following treatment with HBOT and AA. We found that HBOT significantly enhanced the cytotoxic effect of 0.3mM AA.
This data indicates that AA exhibits anti-cancer effects in vitro through an OxS mechanism and that HBOT can enhance this therapeutic effect. Evidence supports the use of these minimally toxic, pro-oxidative, metabolic therapies as adjuvants to the current standard of care.

57) Anti-Cancer Effects of Ascorbic Acid and Hyperbaric Oxygen Therapy in vitro  Janine M. DeBlasi, Nathan P. Ward, Angela M. Poff, Andrew P. Koutnik, Christopher Q. Rogers and Dominic P. D’Agostino
Author Affiliations Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL
To determine if HBOT can enhance the therapeutic effect of AA, we measured measure VM-M3 cell viability following treatment with HBOT and AA. We found that HBOT significantly enhanced the cytotoxic effect of 0.3mM AA (p<0.001). To complete this aim, we will measure VM-M3 cell proliferation following treatment with HBOT, HBOT pre-treatment, and AA.

This data indicates that AA exhibits anti-cancer effect in vitro through an OxS mechanism and that HBOT can enhance this therapeutic effect. These non-toxic, pro-oxidant metabolic therapies should be further investigated as adjuvants to the current standard of care.

58)  Neil Riordan IVC
A comprehensive collection on IVC Literature and Therapies

Weill Cornell Vitamin C Study in Science 2015

59) Yun, Jihye, et al.Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350.6266 (2015): 1391-1396.

60) Buy Paperback on Amazon 2014
Gonzalez, Michael J., and Jorge R. Miranda-Massari. New insights on vitamin C and cancer. Springer New York, 2014. New Insights vitamin C and Cancer Gonzalez Michael Springer 2014

the combination of megadoses of IV ascorbate together with oxygen, vitamin K, lipoic acid, carnitine,magnesium, Coenzyme Q10, and small doses of copper may seem logical as part of a non-toxic treatment protocol for cancer.

61) Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues Qi Chen*†, Michael Graham Espey‡, Murali C. Krishna‡, James B. Mitchell‡, Christopher P. Corpe*, Garry R. Buettner ,Emily Shacter, and Mark Levine*

Effects of Ascorbic Acid on Death of Human Lymphoma Cells.
Human lymphoma cells (JLP-119) were studied in detail to determine the
effects of ascorbate on cell death. Lymphoma cells were selected
because of their sensitivity to ascorbate (Fig. 1A), the suitability of these cells for nuclear staining to characterize the mode of cell
death (16, 19, 28), and the report of a positive clinical response of
lymphoma to i.v. ascorbate (14) (unpublished work). Cells were
incubated for1hwith 0.1–5 mM ascorbate and washed, and Hoechst


PI nuclear staining was performed 18 h later to determine
the amount and type of cell death (Fig. 2 A). Ascorbate induced
concentration-dependent cell death, which was nearly 100% at 2
mM. As ascorbate concentration increased, the pattern of death
changed from apoptosis to pyknosis
necrosis, a pattern suggestive
of H2O2-mediated cell death (19). We determined the time nec-essary for cell death after exposure to 2 mM ascorbate for 1 h (Fig.2B). Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was
 90% at 14 h after exposure. In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate (Fig. 2 C)

vitamin C for Prostate cancer

62) Garcia, Keishla M., et al. “Intravenous Vitamin C and Metabolic Correction as Adjuvant Therapy for prostate Cancer: a Case Report.” (2016).Intravenous Vitamin C for prostate Cancer Case Report Garcia Keishla 2016

Vitamin K3 Menadione Augments IV Vitamin C

63)  Autoschizis: a new word in cancer treatment
Subject: A combination of vitamin C and vitamin K-3 in a 100:1 ratio causes a unique form of cancer cell destruction that has been named autoschizis.

64) Bonilla-Porras, Angelica R., Marlene Jimenez-Del-Rio, and Carlos Velez-Pardo. “Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism.” Cancer cell international 11.1 (2011): 19.

We provide evidence that VK3 and VC alone or in combination induces apoptosis in leukemia cells by a sequential cascade of molecular events involving the production of ROS, simultaneous activation of NF-κB/p53/c-Jun transcription factors, mitochondrial depolarization and caspase-3 activation pathway. These data confirm our hypothesis that VK3 and VC kill leukemia cells by oxidative stress mechanism. Most importantly, VK3 and VC are harmless to lymphocytes, at least under the present in vitro conditions. T

65) High dose intravenous vitamin c treatment in a patient with lung cancer: A case report Michael J. González
School of public health, Medical Sciences Campus, University of Puerto Rico, Ponce PR.

Vitamin C Iv for Ovarian CA – enhances chemo, reduces toxicity

66) (see 28) Ma, Yan, et al. “High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.” Science translational medicine 6.222 (2014): 222ra18-222ra18.High Dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer reduced toxicity of chemo Ma Yan Science translational medicine 2014.

Stem Cell Transplant Pts have Low Vitamin C.
Low Serum Vit C in Leukemia /Lymphoma Patients

67) Ascorbic acid serum levels are reduced in patients with hematological malignancies.  Mirelle J.A.J. Huijskens,a Will K.W.H. Wodzig,b Mateusz Walczak,a Wilfred T.V. Germeraad,a,? and Gerard M.J. Bosa

In this paper we demonstrate that patients treated with chemotherapy and/or hematopoietic stem cell transplantation (HSCT) have highly significant reduced serum ascorbic acid (AA) levels compared to healthy controls. We recently observed in in vitro experiments that growth of both T and NK cells from hematopoietic stem cells is positively influenced by AA. It might be of clinical relevance to study the function and recovery of immune cells after intensive treatment, its correlation to AA serum levels and the possible effect of AA supplementation.

Vitamin C or ascorbic acid (AA), an essential water-soluble vitamin with many functions [1], [2], has a crucial role in cellular immune responses [3]. Patients treated with intensive chemotherapy and/or hematopoietic stem cell transplantation (HSCT) have low immune cell counts for weeks to months [4]. Meanwhile, patients are highly susceptible to infections resulting in morbidity and mortality. We recently observed that in the presence of AA, early hematopoietic progenitors commit and mature into T cells and proliferate faster [5]. Moreover, we showed that AA enhances proliferation and maturation of NK cells [6]. As AA has a major influence on (re)generation of immune cells in vitro, we executed an observational study in which AA serum values of patients with hematological malignancies treated with and without HSCT were compared with those of healthy volunteers to see if low AA levels should be considered of importance regarding immune recovery of these patients.

68)  High-dose Vitamin C (Ascorbic Acid) Therapy in the Treatment of Patients with Advanced Cancer
SATOSHI OHNO1,2, YUMIKO OHNO2, NOBUTAKA SUZUKI1,2, GEN-ICHIRO SOMA3,4,5 and MASAKI INOUE2
Vitamin C (ascorbic acid, ascorbate) has a controversial history in cancer treatment. Emerging evidence indicates that ascorbate in cancer treatment deserves re-examination. As research results concerning ascorbate pharmacokinetics and its mechanisms of action against tumor cells have been published, and as evidence from case studies has continued to mount that ascorbate therapy could be effective if the right protocols were used, interest among physicians and scientists has increased. In this review, high-dose vitamin C therapy in cancer treatment is re-evaluated.

69) Levine, Mark, Michael Graham Espey, and Qi Chen. “Losing and finding a way at C: new promise for pharmacologic ascorbate in cancer treatment.” Free radical biology & medicine 47.1 (2009): 27.

70) Ernestina Marianna De Francesco, Gloria Bonuccelli, Marcello Maggiolini, Federica Sotgia, Michael P. Lisanti. Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs). Oncotarget, 2015; DOI: 10.18632/oncotarget.18428

Alpha Lipoic acid Dosage  600 mg/day IV is safe

71)  Ziegler, Dan, and F. Arnold Gries. “Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy”Diabetes 46.Supplement 2 (1997): S62-S66.
In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM.

72) Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy.  D Ziegler, M Hanefeld, K J Ruhnau, H Hasche, M Lobisch, K Schütte, G Kerum and R Malessa
509 outpatients were randomly assigned to sequential treatment with 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed by 600 mg alpha-lipoic acid three times a day orally for 6 months

Artesenuate for Injection

73)  Artesunat Injection 2009 Artesunat Injection Product Sheet  (Artesunate 60mg/ml) 2009 Neros Pharmaceticals.

Each vial contains 60mg of Artesunate
Each ampoule contains 1 ml of 5% Sodium bicarbonate solution.

Slow IV injection: Dissolve 60mg of Artesunate with 1ml of 5% sodium bicarbonate solution for injection and add 5ml of 0.9% sodium chloride solution for injection before use to make 1ml contains 10mg of Artesunate. Injection must follow immediately soon after dissolution, if the solution appears cloudy or sediment occurs, it should be rejected.

The usual injection dosage for each time: Adult: 1.2mg/kg.
Give 1 dose daily for the 5 consecutive days.

74) POSTER on preparation and Dosing Artesunate: Injectable_Artesunate_poster_guidelines for administration

guidelines for administration of injectable artesunate for severe malaria
6 ml. 3 ml. Artesunate 60 mg solution concentration. 10 mg/ml 20 mg/ml.
Withdraw all the air. from the vial. Artesunate. 60mg.

IV Vitamin C for sepsis

75)  Marik, Paul E., et al. “Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.” CHEST Journal (2016). Hydrocortisone Vitamin C and Thiamine for Sepsis Marik Paul E CHEST 2016

76) Vitamin C and sepsis: The genie is now out of the bottle
Posted by: Thomas E. Levy, MD, JD in Vitamin C Benefits May 22, 2017
naturalhealth365

77) Doctor used vitamin C to save almost 150 patients from certain death of sepsis.   Posted by: Dena Schmidt, staff writer in Vitamin C Benefits April 12, 2017

78) Doctor Turns Up Possible Treatment For Deadly Sepsis
March 23, 201712:01 AM ET Heard on Morning Edition

79) Has sepsis met its match? New treatment may save millions around the world  EVMS Magazine Eastern Virginia Medical School

80) Sepsis treatment protocol  
Vitamin C: 1.5 g IV q 6 hourly for 4 days
Hydrocortisone: 50mg IV push q 6 hourly for 6 days
Thiamine: 200mg IV q 12 hourly for 4 days

Vitamin K3 Sources

81) Global Vitamin K3 (Menadione) Market 2017: Competitive Study and Key Sellers

1 Oxyvit
2 Dirox
3 Brother Enterprises
4 Haining Peace Chemical
5 Mianyang Vanetta Chemical
6 Huasheng Chemical Technology

82) Lee, Min Ho, et al. “Menadione induces G2/M arrest in gastric cancer cells by down-regulation of CDC25C and proteasome mediated degradation of CDK1 and cyclin B1.” American Journal of Translational Research 8.12 (2016): 5246.

B lymphoma sensitive to ascorbate

83) New insights into redox homeostasis as a therapeutic target in B-cell malignancies  Graczyk-Jarzynka, Agnieszkaa; Zagozdzon, Radoslawb,c; Muchowicz, Angelikaa; Siernicka, Martaa,d; Juszczynski, Przemyslawe,*; Firczuk, Malgorzataa,*Current Opinion in Hematology: July 2017 – Volume 24 – Issue 4 – p 393–401

As published by Chen et al.[51], lymphoma cells are much more sensitive to direct exposure to exogenous H2O2 as compared to normal B cells. Accordingly, lymphoma cells are among the most sensitive to L-ascorbate (LD50 ∼ 0.5 mmol/l), which generates exogenous H2O2[51]. Despite the high sensitivity in vitro, the antilymphoma activity of high dose parenteral L-ascorbate in vivo is limited [54].

84)  Chen, Qi, et al. “Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.” Proceedings of the national academy of sciences of the United States of America 102.38 (2005): 13604-13609.

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.

85) Cancer Res. 2010 Nov 15;70(22):9505-14. . Loss of thioredoxin reductase 1 renders tumors highly susceptible to pharmacologic glutathione deprivation. Mandal PK1, Schneider M, Kölle P, Kuhlencordt P, Förster H, Beck H, Bornkamm GW, Conrad M.

Tumor cells generate substantial amounts of reactive oxygen species (ROS), engendering the need to maintain high levels of antioxidants such as thioredoxin (Trx)- and glutathione (GSH)-dependent enzymes. Exacerbating oxidative stress by specifically inhibiting these types of ROS-scavenging enzymes has emerged as a promising chemotherapeutic strategy to kill tumor cells. However, potential redundancies among the various antioxidant systems may constrain this simple approach. Trx1 and thioredoxin reductase 1 (Txnrd1) are upregulated in numerous cancers, and Txnrd1 has been reported to be indispensable for tumorigenesis. However, we report here that genetic ablation of Txnrd1 has no apparent effect on tumor cell behavior based on similar proliferative, clonogenic, and tumorigenic potential. This finding reflects widespread redundancies between the Trx- and GSH-dependent systems based on evidence of a bypass to Txnrd1 deficiency by compensatory upregulation of GSH-metabolizing enzymes. Because the survival and growth of Txnrd1-deficient tumors were strictly dependent on a functional GSH system, Txnrd1-/- tumors were highly susceptible to experimental GSH depletion in vitro and in vivo. Thus, our findings establish for the first time that a concomitant inhibition of the two major antioxidant systems is highly effective in killing tumor, highlighting a promising strategy to combat cancer.

This unique feature of tumor cells can be exploited for “selective toxicity” using the redox modifiers like l-buthionine sulfoximine (BSO), ascorbic acid, arsenic trioxide, imexon, phenethyl isothiocyanate, and motexafin gadolinium that selectively kill the tumor cells by perturbing the redox homeostasis (10).

86) Kiebala, Michelle, et al. “Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach.” Experimental hematology 43.2 (2015): 89-99.

B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined non-toxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin (Trx) system, with non-toxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione (GSH) levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival.

AUR interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle cell lymphoma (MCL) cells. Additionally, there was less toxicity toward normal B-cells. Low AUR concentrations inhibited Trx reductase (TrxR) activity, an effect significantly increased by BSO co-treatment. TrxR over-expression partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited NF-κB signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells over-expressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death.

Together, these findings suggest that AUR+BSO synergistically induce malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies.

Here we show that mantle cell lymphoma (MCL) cells exhibit dramatically reduced viability following combined exposure to AUR and BSO, even at low concentrations of both agents.

87) Bernard, M. P., et al. “Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise.” Current pharmaceutical design 14.21 (2008): 2051-2060.–

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastases. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.  Cox-2 selective inhibitor celecoxib, at a dose of 400 mg/day.  More recently, our laboratory has examined the effects of both celecoxib and OSU03012 on B-CLL, as well as B cell lymphomas [21]. Treatment with either drug significantly attenuated glutathione levels. Glutathione controls damaging reactive oxygen species (ROS) production and low levels of glutathione were associated with decreased malignant B cell viability.

88)  Ou, Junwen, et al. “The safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with stage III-IV non-small cell lung cancer.” European Journal of Pharmaceutical Sciences 109 (2017): 412-418.

Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. We carried out a clinical trial to evaluate the safety and pharmacokinetics of those methods in patients with stage III-IV non-small cell lung cancer (NSCLC). Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I study. They were randomized allocated into 3 groups, and received doses 1.0, 1.2, 1.5 g/kg AA infusions. Participants in the first group received intravenous AA (IVAA) when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. Pharmacokinetic profiles were obtained when they received solely IVAA and when IVAA in combination with mEHT. The process was applied 3 times a week (every other day, weekend days off) for 4 weeks. We found that fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA was significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAA-managed groups. IVAA synergy with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients.

89)
Carr, Anitra C., et al. “Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes.” Critical Care 21 (2017).

Vitamin C is an essential water-soluble nutrient which cannot be synthesised or stored by humans. It is a potent antioxidant with anti-inflammatory and immune-supportive roles. Previous research has indicated that vitamin C levels are depleted in critically ill patients. In this study we have assessed plasma vitamin C concentrations in critically ill patients relative to infection status (septic shock or non-septic) and level of inflammation (C-reactive protein concentrations). Vitamin C status was also assessed relative to daily enteral and parenteral intakes to determine if standard intensive care unit (ICU) nutritional support is adequate to meet the vitamin C needs of critically ill patients.
Methods

Forty-four critically ill patients (24 with septic shock, 17 non-septic, 3 uncategorised) were recruited from the Christchurch Hospital Intensive Care Unit. We measured concentrations of plasma vitamin C and a pro-inflammatory biomarker (C-reactive protein) daily over 4 days and calculated patients’ daily vitamin C intake from the enteral or total parenteral nutrition they received. We compared plasma vitamin C and C-reactive protein concentrations between septic shock and non-septic patients over 4 days using a mixed effects statistical model, and we compared the vitamin C status of the critically ill patients with known vitamin C bioavailability data using a four-parameter log-logistic response model.
Results

Overall, the critically ill patients exhibited hypovitaminosis C (i.e., < 23 μmol/L), with a mean plasma vitamin C concentration of 17.8 ± 8.7 μmol/L; of these, one-third had vitamin C deficiency (i.e., < 11 μmol/L). Patients with hypovitaminosis C had elevated inflammation (C-reactive protein levels; P < 0.05). The patients with septic shock had lower vitamin C concentrations and higher C-reactive protein concentrations than the non-septic patients (P < 0.05). Nearly 40% of the septic shock patients were deficient in vitamin C, compared with 25% of the non-septic patients. These low vitamin C levels were apparent despite receiving recommended intakes via enteral and/or parenteral nutritional therapy (mean 125 mg/d).
Conclusions

Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock.

90) Marik, Paul E., and Michael H. Hooper. “Doctor—your septic patients have scurvy!.” (2018): 23.

Update May 2019

91) Vissers, Margreet CM, and Andrew B. Das. “Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence.”

generation of significant quantities of hydrogen peroxide by the autoxidation of supra-physiological concentrations of ascorbate and stimulation of the 2-oxoglutarate-dependent dioxygenase family of enzymes (2-OGDDs) that have a cofactor requirement for ascorbate. Hydrogen peroxide generation is postulated to generate oxidative stress that preferentially targets cancer cells.

92)  Ang, Abel, et al. “Vitamin C and immune cell function in inflammation and cancer.” Biochemical Society Transactions 46.5 (2018): 1147-1159.

leukocytes accumulate the vitamin to high intracellular concentrations, signalling an important role for it in these cells

93) Badu-Boateng, Charles, and Richard J. Naftalin. “Ascorbate and ferritin interactions: Consequences for iron release in vitro and in vivo and implications for inflammation.” Free Radical Biology and Medicine 133 (2019): 75-87.

94) Ngo, Bryan, et al. “Targeting cancer vulnerabilities with high-dose vitamin C.” Nature Reviews Cancer (2019): 1. Targeting cancer with high dose vitamin C Ngo Bryan Nature Rev Cancer 2019

95) Corti, Alessandro, Eugenia Belcastro, and Alfonso Pompella. “Antitumoral effects of pharmacological ascorbate on gastric cancer cells: GLUT1 expression may not tell the whole story.” Theranostics 8.21 (2018): 6035.

96) Mikirova, Nina, Joseph Casciari, and Ronald Hunninghake. “Continuous intravenous vitamin C in the cancer treatment: re-evaluation of a Phase I clinical study.” Functional Foods in Health and Disease 9.3 (2019): 180-204.

IV Vitamin C  Synergy with Auranofin – Malignant B Cells

97)  Graczyk-Jarzynka, Agnieszka, et al.
“Inhibition of thioredoxin-dependent H2O2 removal sensitizes malignant B-cells to pharmacological ascorbate.” Redox biology 21 (2019): 101062.
auranofin (AUR), the inhibitor of the thioredoxin system that is used as an antirheumatic drug, diminishes the H2O2-scavenging capacity of malignant B-cells and potentiates pharmacological ascorbate anticancer activity in vitro and in vivo.
The addition of AUR to L-ASC-treated cells triggers the accumulation of H2O2 in the cells, which results in iron-dependent cytotoxicity. Importantly, the synergistic effects are observed at as low as 200 µM L-ASC concentrations. In conclusion, we observed strong, synergistic, cancer-selective interaction between L-ASC and auranofin.

98) Hatem, Elie, et al. “Auranofin/vitamin C: a novel drug combination targeting triple-negative breast Cancer.” JNCI: Journal of the National Cancer Institute 111.6 (2018): 597-608.
The in vivo effect of AUF, VC, and two AUF/VC combinations on mice bearing MDA-MB-231 xenografts (n = 5 mice per group) was also evaluated. All statistical tests were two-sided.
Results

AUF targeted simultaneously the thioredoxin and glutathione antioxidant systems. AUF/VC combinations exerted a synergistic and hydrogen peroxide (H2O2)-mediated cytotoxicity toward MDA-MB-231 cells and other breast cancer cell lines. The anticancer potential of AUF/VC combinations was validated in vivo on MDA-MB-231 xenografts in mice without notable side effects. On day 14 of treatments, mean (SD) tumor volumes for the vehicle-treated control group and the two AUF/VC combination–treated groups (A/V1 and A/V2) were 197.67 (24.28) mm3, 15.66 (10.90) mm3, and 10.23 (7.30)mm3, respectively; adjusted P values of the differences between mean tumor volumes of vehicle vs A/V1 groups and vehicle vs A/V2 groups were both less than .001. SILAC proteomics, bioinformatics analysis, and functional experiments linked prostaglandin reductase 1 (PTGR1) expression levels with breast cancer cell sensitivity to AUF/VC combinations.
Conclusion The combination of AUF and VC, two commonly available drugs, could be efficient against triple-negative breast cancer and potentially other cancers with similar redox properties and PTGR1 expression levels. The redox-based anticancer activity of this combination and the discriminatory potential of PTGR1 expression are worth further assessment in preclinical and clinical studies.

Attachments area

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Glen Hyland MD Mayo Clinic IVC, Chemotherapy, Radiation – Are They Compatible? Riordan Clinic

The Scientific Basis of IVC for Cancer Riordan Clinic
VIDEO MICHAEL GONZALEZ U of Puerto Rico

Frank Shallenberger Cancer Case Studies Using Ozone and IVC Protocol – Ozone and IV Vitamin C – video

Jeffrey Dach MD
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