Ascorbic Acid in Cancer Treatment: Let the Phoenix Fly
2018; Cell Press; Volume: 34; Issue: 5 Linguagem: Inglês
10.1016/j.ccell.2018.07.014
ISSN1878-3686
AutoresNiraj Shenoy, Edward T. Creagan, Thomas E. Witzig, Mark Levine,
Tópico(s)Nanoparticles: synthesis and applications
ResumoVitamin C (ascorbic acid, ascorbate), despite controversy, has re-emerged as a promising anti-cancer agent. Recent knowledge of intravenous ascorbate pharmacokinetics and discovery of unexpected mechanisms of ascorbate action have spawned many investigations. Two mechanisms of anti-cancer activity with ascorbate have gained prominence: hydrogen peroxide-induced oxidative stress and DNA demethylation mediated by ten-eleven translocation enzyme activation. Here, we highlight salient aspects of the evolution of ascorbate in cancer treatment, provide insights into the pharmacokinetics of ascorbate, describe mechanisms of its anti-cancer activity in relation to the pharmacokinetics, outline promising preclinical and clinical evidence, and recommend future directions. Vitamin C (ascorbic acid, ascorbate), despite controversy, has re-emerged as a promising anti-cancer agent. Recent knowledge of intravenous ascorbate pharmacokinetics and discovery of unexpected mechanisms of ascorbate action have spawned many investigations. Two mechanisms of anti-cancer activity with ascorbate have gained prominence: hydrogen peroxide-induced oxidative stress and DNA demethylation mediated by ten-eleven translocation enzyme activation. Here, we highlight salient aspects of the evolution of ascorbate in cancer treatment, provide insights into the pharmacokinetics of ascorbate, describe mechanisms of its anti-cancer activity in relation to the pharmacokinetics, outline promising preclinical and clinical evidence, and recommend future directions. Like a phoenix, ascorbic acid as an anti-cancer agent has had a spectacular rise, fall, and re-emergence. In the 1970s Ewan Cameron, joined by Linus Pauling, described retrospectively and in case reports that patients with advanced cancer had survival benefit and symptomatic relief using high-dose ascorbate (10 g/day) (Cameron and Campbell, 1974Cameron E. Campbell A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer.Chem. Biol. Interact. 1974; 9: 285-315Crossref PubMed Scopus (241) Google Scholar, Cameron and Pauling, 1976Cameron E. Pauling L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer.Proc. Natl. Acad. Sci. USA. 1976; 73: 3685-3689Crossref PubMed Scopus (480) Google Scholar, Cameron and Pauling, 1978Cameron E. Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer.Proc. Natl. Acad. Sci. USA. 1978; 75: 4538-4542Crossref PubMed Scopus (363) Google Scholar). Subsequently, two rigorous double-blind placebo-controlled prospective trials performed at the Mayo Clinic using the same dose of ascorbate failed to confirm these results, and oral ascorbate as an anti-cancer agent was roundly dismissed (Creagan et al., 1979Creagan E.T. Moertel C.G. O'Fallon J.R. Schutt A.J. O'Connell M.J. Rubin J. Frytak S. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial.N. Engl. J. Med. 1979; 301: 687-690Crossref PubMed Scopus (431) Google Scholar, Moertel et al., 1985Moertel C.G. Fleming T.R. Creagan E.T. Rubin J. O'Connell M.J. Ames M.M. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison.N. Engl. J. Med. 1985; 312: 137-141Crossref PubMed Scopus (448) Google Scholar, Wittes, 1985Wittes R.E. Vitamin C and cancer.N. Engl. J. Med. 1985; 312: 178-179Crossref PubMed Scopus (55) Google Scholar). About two decades ago, new knowledge of ascorbate pharmacokinetics spawned the discovery of anti-cancer mechanisms of ascorbate action (Table 1). To provide a foundational basis for dietary recommendations for ascorbic acid, healthy subjects underwent intensive clinical pharmacokinetics and physiology studies, the first studies of this kind for any vitamin (Levine et al., 1996Levine M. Conry-Cantilena C. Wang Y. Welch R.W. Washko P.W. Dhariwal K.R. Park J.B. Lazarev A. Graumlich J.F. King J. Cantilena L.R. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.Proc. Natl. Acad. Sci. USA. 1996; 93: 3704-3709Crossref PubMed Scopus (1005) Google Scholar, Levine et al., 2001Levine M. Wang Y. Katz A. Eck P. Kwon O. Chen S. Lee J.H. Padayatty S.J. Ideal vitamin C intake.BioFactors. 2001; 15: 71-74Crossref PubMed Scopus (13) Google Scholar). Findings were that oral doses of ascorbic acid over an ∼80-fold dose range produced plasma concentrations that were tightly controlled by limited gastrointestinal absorption, saturated tissue transporters, and renal reabsorption and excretion (Corpe et al., 2010Corpe C.P. Tu H. Eck P. Wang J. Faulhaber-Walter R. Schnermann J. Margolis S. Padayatty S. Sun H. Wang Y. et al.Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice.J. Clin. Invest. 2010; 120: 1069-1083Crossref PubMed Scopus (123) Google Scholar, Corpe et al., 2013Corpe C.P. Eck P. Wang J. Al-Hasani H. Levine M. Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8.J. Biol. Chem. 2013; 288: 9092-9101Crossref PubMed Scopus (93) Google Scholar, Levine et al., 1996Levine M. Conry-Cantilena C. Wang Y. Welch R.W. Washko P.W. Dhariwal K.R. Park J.B. Lazarev A. Graumlich J.F. King J. Cantilena L.R. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.Proc. Natl. Acad. Sci. USA. 1996; 93: 3704-3709Crossref PubMed Scopus (1005) Google Scholar, Levine et al., 2001Levine M. Wang Y. Katz A. Eck P. Kwon O. Chen S. Lee J.H. Padayatty S.J. Ideal vitamin C intake.BioFactors. 2001; 15: 71-74Crossref PubMed Scopus (13) Google Scholar, Padayatty et al., 2004Padayatty S.J. Sun H. Wang Y. Riordan H.D. Hewitt S.M. Katz A. Wesley R.A. Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use.Ann. Intern. Med. 2004; 140: 533-537Crossref PubMed Scopus (643) Google Scholar, Sotiriou et al., 2002Sotiriou S. Gispert S. Cheng J. Wang Y. Chen A. Hoogstraten-Miller S. Miller G.F. Kwon O. Levine M. Guttentag S.H. Nussbaum R.L. Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival.Nat. Med. 2002; 8: 514-517Crossref PubMed Scopus (289) Google Scholar). Intravenous (i.v.) administration bypassed tight control until the kidney restored homeostasis. Depending on dose and infusion time, i.v. ascorbate produced plasma levels that were hundreds of times higher than those produced by the maximum tolerated dose of oral ascorbate (Chen et al., 2008Chen Q. Espey M.G. Sun A.Y. Pooput C. Kirk K.L. Krishna M.C. Khosh D.B. Drisko J. Levine M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 11105-11109Crossref PubMed Scopus (630) Google Scholar, Hoffer et al., 2008Hoffer L.J. Levine M. Assouline S. Melnychuk D. Padayatty S.J. Rosadiuk K. Rousseau C. Robitaille L. Miller Jr., W.H. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy.Ann. Oncol. 2008; 19: 1969-1974Crossref PubMed Scopus (287) Google Scholar, Padayatty and Levine, 2000Padayatty S.J. Levine M. Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity.J. Am. Coll. Nutr. 2000; 19: 423-425Crossref PubMed Scopus (79) Google Scholar, Padayatty et al., 2004Padayatty S.J. Sun H. Wang Y. Riordan H.D. Hewitt S.M. Katz A. Wesley R.A. Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use.Ann. Intern. Med. 2004; 140: 533-537Crossref PubMed Scopus (643) Google Scholar, Park et al., 2009Park C.H. Kimler B.F. Yi S.Y. Park S.H. Kim K. Jung C.W. Kim S.H. Lee E.R. Rha M. Kim S. et al.Depletion of L-ascorbic acid alternating with its supplementation in the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes.Eur. J. Haematol. 2009; 83: 108-118Crossref PubMed Scopus (14) Google Scholar). These pharmacokinetics data provided a potential explanation to the conflicting cancer treatment outcomes, because no one at the time knew that i.v. and oral ascorbic acid behaved so differently. Cameron administered 10 g of ascorbate intravenously as well as orally, while Mayo investigators used oral ascorbate alone. With pharmacokinetics as a foundation, it was shown that only ascorbic acid at pharmacologic concentrations from i.v. dosing, and that would not occur from oral dosing, acted as prodrug for hydrogen peroxide (H2O2) formation in the extracellular space (Chen et al., 2005Chen Q. Espey M.G. Krishna M.C. Mitchell J.B. Corpe C.P. Buettner G.R. Shacter E. Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.Proc. Natl. Acad. Sci. USA. 2005; 102: 13604-13609Crossref PubMed Scopus (798) Google Scholar, Chen et al., 2007Chen Q. Espey M.G. Sun A.Y. Lee J.H. Krishna M.C. Shacter E. Choyke P.L. Pooput C. Kirk K.L. Buettner G.R. Levine M. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo.Proc. Natl. Acad. Sci. USA. 2007; 104: 8749-8754Crossref PubMed Scopus (511) Google Scholar). Pharmacologic, but not physiologic, ascorbic acid was selectively toxic to cancer cells in vitro and in vivo (Chen et al., 2005Chen Q. Espey M.G. Krishna M.C. Mitchell J.B. Corpe C.P. Buettner G.R. Shacter E. Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.Proc. Natl. Acad. Sci. USA. 2005; 102: 13604-13609Crossref PubMed Scopus (798) Google Scholar, Chen et al., 2008Chen Q. Espey M.G. Sun A.Y. Pooput C. Kirk K.L. Krishna M.C. Khosh D.B. Drisko J. Levine M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 11105-11109Crossref PubMed Scopus (630) Google Scholar, Verrax and Calderon, 2009Verrax J. Calderon P.B. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects.Free Radic. Biol. Med. 2009; 47: 32-40Crossref PubMed Scopus (186) Google Scholar). Additionally, the requisite pharmacologic ascorbic acid concentrations are achieved predictably and safely in humans (Chen et al., 2008Chen Q. Espey M.G. Sun A.Y. Pooput C. Kirk K.L. Krishna M.C. Khosh D.B. Drisko J. Levine M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 11105-11109Crossref PubMed Scopus (630) Google Scholar, Hoffer et al., 2008Hoffer L.J. Levine M. Assouline S. Melnychuk D. Padayatty S.J. Rosadiuk K. Rousseau C. Robitaille L. Miller Jr., W.H. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy.Ann. Oncol. 2008; 19: 1969-1974Crossref PubMed Scopus (287) Google Scholar, Monti et al., 2012Monti D.A. Mitchell E. Bazzan A.J. Littman S. Zabrecky G. Yeo C.J. Pillai M.V. Newberg A.B. Deshmukh S. Levine M. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.PLoS One. 2012; 7: e29794Crossref PubMed Scopus (183) Google Scholar, Padayatty et al., 2010Padayatty S.J. Sun A.Y. Chen Q. Espey M.G. Drisko J. Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects.PLoS One. 2010; 5: e11414Crossref PubMed Scopus (211) Google Scholar, Welsh et al., 2013Welsh J.L. Wagner B.A. van't Erve T.J. Zehr P.S. Berg D.J. Halfdanarson T.R. Yee N.S. Bodeker K.L. Du J. Roberts 2nd, L.J. et al.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. 2013; 71: 765-775Crossref PubMed Scopus (198) Google Scholar). In animal models, pharmacologic ascorbate either has anti-cancer activity similar to conventional chemotherapy or synergizes with it (Espey et al., 2011Espey M.G. Chen P. Chalmers B. Drisko J. Sun A.Y. Levine M. Chen Q. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer.Free Radic. Biol. Med. 2011; 50: 1610-1619Crossref PubMed Scopus (135) Google Scholar, Ma et al., 2014Ma Y. Chapman J. Levine M. Polireddy K. Drisko J. Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.Sci. Transl. Med. 2014; 6: 222ra218Crossref Scopus (301) Google Scholar, Serrano et al., 2015Serrano O.K. Parrow N.L. Violet P.C. Yang J. Zornjak J. Basseville A. Levine M. Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model.Free Radic. Biol. Med. 2015; 87: 193-203Crossref PubMed Scopus (19) Google Scholar, Xia et al., 2017Xia J. Xu H. Zhang X. Allamargot C. Coleman K.L. Nessler R. Frech I. Tricot G. Zhan F. Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid.EBioMedicine. 2017; 18: 41-49Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Conversely, there are no data showing that pharmacologic ascorbate interferes with chemotherapy. Early-phase clinical trials indicate that i.v. ascorbate at 1 g/kg over 90–120 min two to three times weekly is well tolerated and may enhance chemosensitivity as well as decrease chemotherapy-related side effects (Carr et al., 2014Carr A.C. Vissers M.C. Cook J.S. The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life.Front. Oncol. 2014; 4: 283Crossref PubMed Scopus (58) Google Scholar, Hoffer et al., 2015Hoffer L.J. Robitaille L. Zakarian R. Melnychuk D. Kavan P. Agulnik J. Cohen V. Small D. Miller Jr., W.H. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.PLoS One. 2015; 10: e0120228Crossref PubMed Scopus (72) Google Scholar, Ma et al., 2014Ma Y. Chapman J. Levine M. Polireddy K. Drisko J. Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.Sci. Transl. Med. 2014; 6: 222ra218Crossref Scopus (301) Google Scholar, Monti et al., 2012Monti D.A. Mitchell E. Bazzan A.J. Littman S. Zabrecky G. Yeo C.J. Pillai M.V. Newberg A.B. Deshmukh S. Levine M. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.PLoS One. 2012; 7: e29794Crossref PubMed Scopus (183) Google Scholar, Schoenfeld et al., 2017Schoenfeld J.D. Sibenaller Z.A. Mapuskar K.A. Wagner B.A. Cramer-Morales K.L. Furqan M. Sandhu S. Carlisle T.L. Smith M.C. Abu Hejleh T. et al.O2- and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate.Cancer Cell. 2017; 31: 487-500.e8Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, Shim et al., 2014Shim E.H. Livi C.B. Rakheja D. Tan J. Benson D. Parekh V. Kho E.Y. Ghosh A.P. Kirkman R. Velu S. et al.L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.Cancer Discov. 2014; 4: 1290-1298Crossref PubMed Scopus (188) Google Scholar, Stephenson et al., 2013Stephenson C.M. Levin R.D. Spector T. Lis C.G. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.Cancer Chemother. Pharmacol. 2013; 72: 139-146Crossref PubMed Scopus (166) Google Scholar, Welsh et al., 2013Welsh J.L. Wagner B.A. van't Erve T.J. Zehr P.S. Berg D.J. Halfdanarson T.R. Yee N.S. Bodeker K.L. Du J. Roberts 2nd, L.J. et al.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. 2013; 71: 765-775Crossref PubMed Scopus (198) Google Scholar).Table 1Evolution of Ascorbic Acid Studies in CancerCameron/Pauling StudiesMayo Clinic StudiesVitamin C Pharmacokinetics and Early-Phase Clinical TrialsStudies on H2O2 Mechanism of Anti-cancer ActivityStudies on Epigenetic Mechanism of Anti-cancer ActivityEwan Cameron, joined by Linus Pauling, described retrospectively and in case reports that patients with advanced cancer had survival benefit and symptomatic relief using high-dose ascorbate (10 g/day i.v. followed by oral)(Cameron and Campbell, 1974Cameron E. Campbell A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer.Chem. Biol. Interact. 1974; 9: 285-315Crossref PubMed Scopus (241) Google Scholar, Cameron and Pauling, 1976Cameron E. Pauling L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer.Proc. Natl. Acad. Sci. USA. 1976; 73: 3685-3689Crossref PubMed Scopus (480) Google Scholar, Cameron and Pauling, 1978Cameron E. Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer.Proc. Natl. Acad. Sci. USA. 1978; 75: 4538-4542Crossref PubMed Scopus (363) Google Scholar)Two rigorous double-blind placebo-controlled prospective trials performed at the Mayo Clinic using the same dose of ascorbate, but orally only, failed to confirm these results, and oral ascorbate was dismissed as an anti-cancer agent(Creagan et al., 1979Creagan E.T. Moertel C.G. O'Fallon J.R. Schutt A.J. O'Connell M.J. Rubin J. Frytak S. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial.N. Engl. J. Med. 1979; 301: 687-690Crossref PubMed Scopus (431) Google Scholar, Moertel et al., 1985Moertel C.G. Fleming T.R. Creagan E.T. Rubin J. O'Connell M.J. Ames M.M. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison.N. Engl. J. Med. 1985; 312: 137-141Crossref PubMed Scopus (448) Google Scholar, Wittes, 1985Wittes R.E. Vitamin C and cancer.N. Engl. J. Med. 1985; 312: 178-179Crossref PubMed Scopus (55) Google Scholar)Oral ascorbic acid over an 80-fold dose range was found to produce plasma concentrations that were tightly regulated by gastrointestinal absorption, but i.v. administration bypassed this control until the kidney restored homeostasis. Maximum tolerated doses of oral (∼18 g daily) ascorbate produced plasma concentrations of ∼100–200 μM. Intravenous ascorbate was found to produce plasma levels hundreds of times higher than those produced by the maximum tolerated dose of oral ascorbate(Hoffer et al., 2008Hoffer L.J. Levine M. Assouline S. Melnychuk D. Padayatty S.J. Rosadiuk K. Rousseau C. Robitaille L. Miller Jr., W.H. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy.Ann. Oncol. 2008; 19: 1969-1974Crossref PubMed Scopus (287) Google Scholar, Padayatty and Levine, 2000Padayatty S.J. Levine M. Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity.J. Am. Coll. Nutr. 2000; 19: 423-425Crossref PubMed Scopus (79) Google Scholar, Padayatty et al., 2004Padayatty S.J. Sun H. Wang Y. Riordan H.D. Hewitt S.M. Katz A. Wesley R.A. Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use.Ann. Intern. Med. 2004; 140: 533-537Crossref PubMed Scopus (643) Google Scholar, Park et al., 2009Park C.H. Kimler B.F. Yi S.Y. Park S.H. Kim K. Jung C.W. Kim S.H. Lee E.R. Rha M. Kim S. et al.Depletion of L-ascorbic acid alternating with its supplementation in the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes.Eur. J. Haematol. 2009; 83: 108-118Crossref PubMed Scopus (14) Google Scholar)Early-phase clinical trials indicate that i.v. ascorbate at 1 g/kg over 1.5–2 hr two to three times weekly is well tolerated and may enhance chemosensitivity as well as decrease chemotherapy-related side effects(Carr et al., 2014Carr A.C. Vissers M.C. Cook J.S. The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life.Front. Oncol. 2014; 4: 283Crossref PubMed Scopus (58) Google Scholar, Hoffer et al., 2015Hoffer L.J. Robitaille L. Zakarian R. Melnychuk D. Kavan P. Agulnik J. Cohen V. Small D. Miller Jr., W.H. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.PLoS One. 2015; 10: e0120228Crossref PubMed Scopus (72) Google Scholar, Ma et al., 2014Ma Y. Chapman J. Levine M. Polireddy K. Drisko J. Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.Sci. Transl. Med. 2014; 6: 222ra218Crossref Scopus (301) Google Scholar, Monti et al., 2012Monti D.A. Mitchell E. Bazzan A.J. Littman S. Zabrecky G. Yeo C.J. Pillai M.V. Newberg A.B. Deshmukh S. Levine M. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.PLoS One. 2012; 7: e29794Crossref PubMed Scopus (183) Google Scholar, Schoenfeld et al., 2017Schoenfeld J.D. Sibenaller Z.A. Mapuskar K.A. Wagner B.A. Cramer-Morales K.L. Furqan M. Sandhu S. Carlisle T.L. Smith M.C. Abu Hejleh T. et al.O2- and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate.Cancer Cell. 2017; 31: 487-500.e8Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, Shim et al., 2014Shim E.H. Livi C.B. Rakheja D. Tan J. Benson D. Parekh V. Kho E.Y. Ghosh A.P. Kirkman R. Velu S. et al.L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.Cancer Discov. 2014; 4: 1290-1298Crossref PubMed Scopus (188) Google Scholar, Stephenson et al., 2013Stephenson C.M. Levin R.D. Spector T. Lis C.G. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.Cancer Chemother. Pharmacol. 2013; 72: 139-146Crossref PubMed Scopus (166) Google Scholar, Welsh et al., 2013Welsh J.L. Wagner B.A. van't Erve T.J. Zehr P.S. Berg D.J. Halfdanarson T.R. Yee N.S. Bodeker K.L. Du J. Roberts 2nd, L.J. et al.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. 2013; 71: 765-775Crossref PubMed Scopus (198) Google Scholar)Plasma concentrations achieved by i.v. dosing found to act as a prodrug for hydrogen peroxide (H2O2) in the extracellular space. Pharmacologic, but not physiologic, ascorbic acid was selectively toxic to cancer cells in vitro and in vivo(Chen et al., 2005Chen Q. Espey M.G. Krishna M.C. Mitchell J.B. Corpe C.P. Buettner G.R. Shacter E. Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.Proc. Natl. Acad. Sci. USA. 2005; 102: 13604-13609Crossref PubMed Scopus (798) Google Scholar, Chen et al., 2007Chen Q. Espey M.G. Sun A.Y. Lee J.H. Krishna M.C. Shacter E. Choyke P.L. Pooput C. Kirk K.L. Buettner G.R. Levine M. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo.Proc. Natl. Acad. Sci. USA. 2007; 104: 8749-8754Crossref PubMed Scopus (511) Google Scholar, Chen et al., 2008Chen Q. Espey M.G. Sun A.Y. Pooput C. Kirk K.L. Krishna M.C. Khosh D.B. Drisko J. Levine M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 11105-11109Crossref PubMed Scopus (630) Google Scholar, Verrax and Calderon, 2009Verrax J. Calderon P.B. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects.Free Radic. Biol. Med. 2009; 47: 32-40Crossref PubMed Scopus (186) Google Scholar, Espey et al., 2011Espey M.G. Chen P. Chalmers B. Drisko J. Sun A.Y. Levine M. Chen Q. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer.Free Radic. Biol. Med. 2011; 50: 1610-1619Crossref PubMed Scopus (135) Google Scholar, Ma et al., 2014Ma Y. Chapman J. Levine M. Polireddy K. Drisko J. Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.Sci. Transl. Med. 2014; 6: 222ra218Crossref Scopus (301) Google Scholar, Serrano et al., 2015Serrano O.K. Parrow N.L. Violet P.C. Yang J. Zornjak J. Basseville A. Levine M. Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model.Free Radic. Biol. Med. 2015; 87: 193-203Crossref PubMed Scopus (19) Google Scholar, Xia et al., 2017Xia J. Xu H. Zhang X. Allamargot C. Coleman K.L. Nessler R. Frech I. Tricot G. Zhan F. Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid.EBioMedicine. 2017; 18: 41-49Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar)Ascorbate functions as a cofactor and increases the activity of the ten-eleven translocation (TET) enzymes causing DNA demethylationThis function has been found to result in the re-expression of tumor-suppressor genes in cancer cells, promotion of stem cell differentiation and inhibition of leukemogenesis, and enhancement of DNA methyltransferase inhibitor (DNMTi)-induced immune signals via increased expression of endogenous retrovirus transcripts(Agathocleous et al., 2017Agathocleous M. Meacham C.E. Burgess R.J. Piskounova E. Zhao Z. Crane G.M. Cowin B.L. Bruner E. Murphy M.M. Chen W. et al.Ascorbate regulates haematopoietic stem cell function and leukaemogenesis.Nature. 2017; 549: 476-481Crossref PubMed Scopus (309) Google Scholar, Cimmino et al., 2017Cimmino L. Dolgalev I. Wang Y. Yoshimi A. 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Epigenetic reprogramming of melanoma cells by vitamin C treatment.Clin. Epigenetics. 2015; 7: 51Crossref PubMed Scopus (57) Google Scholar) Open table in a new tab Ascorbate physiology and pharmacokinetics findings are the backbone of these observations. Nevertheless, extracellular H2O2 formation generated by pharmacologic ascorbate may not explain all pharmacology actions. As one example, recent findings implicate oxidized ascorbic acid, dehydroascorbic acid, as the mediator of cancer cell death in specific engineered cell lines (Yun et al., 2015Yun J. Mullarky E. Lu C. Bosch K.N. Kavalier A. Rivera K. Roper J. Chio II, Giannopoulou E.G. Rago C. et al.Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.Science. 2015; 350: 1391-1396Crossref PubMed Scopus (583) Google Scholar). Although the conclusions are attractive, extracellular H2O2 generation from pharmacologic ascorbate could well account for the observations, a possibility not tested. Other investigators found no effects of dehydroascorbic acid on cancer cells using a variety of cell types (Chen et al., 2005Chen Q. Espey M.G. Krishna M.C. Mitchell J.B. Corpe C.P. Buettner G.R. Shacter E. Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.Proc. Natl. Acad. Sci. USA. 2005; 102: 13604-13609Crossref PubMed Scopus (798) Google Scholar, Ma et al., 2014Ma Y. Chapman J. Levine M. Polireddy K. Drisko J. Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.Sci. Transl. Med. 2014; 6: 222ra218Crossref Scopus (301) Google Scholar, Schoenfeld et al., 2017Schoenfeld J.D. Sibenaller Z.A. Mapuskar K.A. Wagner B.A. Cramer-Morales K.L. Furqan M. Sandhu S. Carlisle T.L. Smith M.C. Abu Hejleh T. et al.O2- and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate.Cancer Cell. 2017; 31: 487-500.e8Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). Clinically, dehydroascorbic acid currently would not be administered because of potential pancreatic toxicity (Patterson and Lazarow, 1950Patterson J.W. Lazarow A. Sulfhydryl protection against dehydroascorbic acid diabetes.J. Biol. Chem. 1950; 186: 141-144PubMed Google Scholar). As another example, we should not forget Ewan Cameron's cases. Prior to publications with Linus Pauling, Cameron reported a case series where unexpected tumor responses were observed, using i.v. ascorbate at 10 g daily for 7–10 days followed by oral ascorbate at 10 g daily (Cameron and Campbell, 1974Cameron E. Ca
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