Increasing superoxide production and the labile iron pool in tumor cells may sensitize them to extracellular ascorbate

Frontiers in Oncology

Volumn 4, Issue SEP, 2014, Pages

  McCarty, Mark F ^a   Contreras, Francisco ^a  

^a Oasis of Hope Hospital   (Mexico)

Author keywords

[No Author keywords available]

Indexed keywords

ASCORBIC ACID; DICHLOROACETIC ACID; HYDROGEN PEROXIDE; I KAPPA B KINASE BETA; IRON; SUPEROXIDE;

ANTIOXIDANT ACTIVITY; GENETIC TRANSCRIPTION; GLUCOSE TRANSPORT; GLYCOLYSIS; HUMAN; KETOACIDOSIS; LETHALITY; MITOCHONDRION; NONHUMAN; OXIDATIVE STRESS; OXYGENATION; REVIEW; SIGNAL TRANSDUCTION; TUMOR CELL;

EID: 84907029269     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2014.00249     Document Type: Review

References (130)

1. Padayatty SJ, Sun H, Wang Y et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004 April 6;140(7):533-7.
2. Hoffer LJ, Levine M, Assouline S et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 2008 November;19(11):1969-74.
3. Chen Q, Espey MG, Krishna MC et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A 2005 September 20;102(38):13604-9.
4. Chen Q, Espey MG, Sun AY et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A 2007 May 22;104(21):8749-54.
5. Chen Q, Espey MG, Sun AY et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 2008 August 12;105(32):11105-9.
6. Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med 2009 July 1;47(1):32-40.
7. Hoffer LJ, Levine M, Assouline S et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 2008 November;19(11):1969-74.
8. McCarty MF, Barroso-Aranda J, Contreras F. A two-phase strategy for treatment of oxidantdependent cancers. Med Hypotheses 2007;69(3):489-96.
9. Ranzato E, Biffo S, Burlando B. Selective ascorbate toxicity in malignant mesothelioma: a redox Trojan mechanism. Am J Respir Cell Mol Biol 2011 January;44(1):108-17.
10. Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med 2009 July 1;47(1):32-40.
11. Aykin-Burns N, Ahmad IM, Zhu Y, Oberley LW, Spitz DR. Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J 2009 February 15;418(1):29-37.
12. Springer EL. Comparative study of the cytoplasmic organelles of epithelial cell lines derived from human carcinomas and nonmalignant tissues. Cancer Res 1980 March;40(3):803-17.
13. Copeland WC, Wachsman JT, Johnson FM, Penta JS. Mitochondrial DNA alterations in cancer.Cancer Invest 2002;20(4):557-69.
14. Chen EI. Mitochondrial dysfunction and cancer metastasis. J Bioenerg Biomembr 2012 December;44(6):619-22.
15. Wallace DC. Mitochondria and cancer. Nat Rev Cancer 2012 October;12(10):685-98.
16. Corazao-Rozas P, Guerreschi P, Jendoubi M et al. Mitochondrial oxidative stress is the Achille'sheel of melanoma cells resistant to Braf-mutant inhibitor. Oncotarget 2013 November;4(11):1986-98.
17. Weyemi U, Redon CE, Parekh PR, Dupuy C, Bonner WM. NADPH Oxidases NOXs and DUOXs as putative targets for cancer therapy. Anticancer Agents Med Chem 2013 March;13(3):502-14.
18. Ushio-Fukai M. Localizing NADPH oxidase-derived ROS. Sci STKE 2006 August 22;2006(349):re8.
19. Gordillo G, Fang H, Park H, Roy S. Nox-4-dependent nuclear H2O2 drives DNA oxidation resulting in 8-OHdG as urinary biomarker and hemangioendothelioma formation. Antioxid Redox Signal 2010 April 15;12(8):933-43.
20. Paletta-Silva R, Rocco-Machado N, Meyer-Fernandes JR. NADPH oxidase biology and the regulation of tyrosine kinase receptor signaling and cancer drug cytotoxicity. Int J Mol Sci 2013;14(2):3683-704.
21. Karisch R, Neel BG. Methods to monitor classical protein-tyrosine phosphatase oxidation. FEBSJ 2013 January;280(2):459-75.
22. Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ. Effect of ascorbate on the activity of hypoxiainducible factor in cancer cells. Cancer Res 2003 April 15;63(8):1764-8.
23. Page EL, Chan DA, Giaccia AJ, Levine M, Richard DE. Hypoxia-inducible factor-1alpha stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion.Mol Biol Cell 2008 January;19(1):86-94.
24. Lisy K, Peet DJ. Turn me on: regulating HIF transcriptional activity. Cell Death Differ 2008 April;15(4):642-9.
25. Kuiper C, Molenaar IG, Dachs GU, Currie MJ, Sykes PH, Vissers MC. Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res 2010 July 15;70(14):5749-58.
26. Chandel NS, McClintock DS, Feliciano CE et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: amechanism of O2 sensing. J Biol Chem 2000 August 18;275(33):25130-8.
27. Brar SS, Kennedy TP, Quinn M, Hoidal JR. Redox signaling of NF-kappaB by membrane NAD(P)H oxidases in normal and malignant cells. Protoplasma 2003 May;221(1-2):117-27.
28. Dreher D, Junod AF. Role of oxygen free radicals in cancer development. Eur J Cancer 1996 January;32A(1):30-8.
29. McCarty MF, Barroso-Aranda J, Contreras F. Practical strategies for suppressing hypoxiainducible factor activity in cancer therapy. Med Hypotheses 2010 May;74(5):789-97.
30. Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007 June;39(3):231-4.
31. Stubbs M, Griffiths JR. The altered metabolism of tumors: HIF-1 and its role in the Warburg effect. Adv Enzyme Regul 2010;50(1):44-55.
32. Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 2008 October 17;283(42):28106-14.
33. Kirito K, Hu Y, Komatsu N. HIF-1 prevents the overproduction of mitochondrial ROS after cytokine stimulation through induction of PDK-1. Cell Cycle 2009 September 1;8(17):2844-9.
34. Semenza GL. Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta 2011 July;1813(7):1263-8.
35. Simons AL, Mattson DM, Dornfeld K, Spitz DR. Glucose deprivation-induced metabolic oxidative stress and cancer therapy. J Cancer Res Ther 2009 September;5 Suppl 1:S2-S6.
36. O'Donnell-Tormey J, Nathan CF, Lanks K, DeBoer CJ, de la Harpe J. Secretion of pyruvate. An antioxidant defense of mammalian cells. J Exp Med 1987 February 1;165(2):500-14.
37. Kao KK, Fink MP. The biochemical basis for the anti-inflammatory and cytoprotective actions of ethyl pyruvate and related compounds. Biochem Pharmacol 2010 July 15;80(2):151-9.
38. Sinnberg T, Noor S, Venturelli S et al. The ROS-induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF-1alpha in the NCI60 cancer cell lines. J Cell Mol Med 2014 March;18(3):530-41.
39. Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 2008 October 7;99(7):989-94.
40. Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol 2013;3:38.
41. Michelakis ED, Sutendra G, Dromparis P et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010 May 12;2(31):31ra34.
42. Sorokina LV, Pyatchanina TV, Didenko GV, Kaplia AA, Khyzhnyak SV. The influence of sodium dichloroacetate on the oxidative processes in sarcoma 37. Exp Oncol 2011 December;33(4):216-21.
43. Kluza J, Corazao-Rozas P, Touil Y et al. Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeuticactivity of pro-oxidants. Cancer Res 2012 October 1;72(19):5035-47.
44. McFate T, Mohyeldin A, Lu H et al. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 2008 August 15;283(33):22700-8.
45. Abdelmalak M, Lew A, Ramezani R et al. Long-term safety of dichloroacetate in congenitallactic acidosis. Mol Genet Metab 2013 June;109(2):139-43.
46. Dunbar EM, Coats BS, Shroads AL et al. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest New Drugs 2014 June;32(3):452-64.
47. Allen BG, Bhatia SK, Buatti JM et al. Ketogenic diets enhance oxidative stress and radio-chemotherapy responses in lung cancer xenografts. Clin Cancer Res 2013 July 15;19(14):3905-13.
48. Zwicker F, Kirsner A, Peschke P et al. Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo. Strahlenther Onkol 2013 August;189(8):684-92.
49. Maevsky E, Ivanitsky G, Bogdanova L et al. Clinical results of Perftoran application: present and future. Artif Cells Blood Substit Immobil Biotechnol 2005;33(1):37-46.
50. Maevsky E, Ivanitsky G, Bogdanova L et al. Clinical results of Perftoran application: present and future. Artif Cells Blood Substit Immobil Biotechnol 2005;33(1):37-46.
51. Mayer R, Hamilton-Farrell MR, van der Kleij AJ et al. Hyperbaric oxygen and radiotherapy.Strahlenther Onkol 2005 February;181(2):113-23.
52. Moen I, Stuhr LE. Hyperbaric oxygen therapy and cancer--a review. Target Oncol 2012 December;7(4):233-42.
53. Yoshikawa T, Kokura S, Tainaka K et al. The role of active oxygen species and lipid peroxidation in the antitumor effect of hyperthermia. Cancer Res 1993 May 15;53(10Suppl):2326-9.
54. Moriyama-Gonda N, Igawa M, Shiina H, Urakami S, Shigeno K, Terashima M. Modulation of heat-induced cell death in PC-3 prostate cancer cells by the antioxidant inhibitor diethyldithiocarbamate. BJU Int 2002 August;90(3):317-25.
55. Lehmann K, Rickenbacher A, Jang JH et al. New insight into hyperthermic intraperitoneal chemotherapy: induction of oxidative stress dramatically enhanced tumor killing in in vitro and in vivo models. Ann Surg 2012 November;256(5):730-7.
56. Venkataraman S, Wagner BA, Jiang X et al. Overexpression of manganese superoxide dismutase promotes the survival of prostate cancer cells exposed to hyperthermia. Free Radic Res 2004 October;38(10):1119-32.
57. Moriyama-Gonda N, Igawa M, Shiina H, Urakami S, Terashima M. Decreased survival of prostate cancer cells in vitro by combined treatment of heat and an antioxidant inhibitor diethyldithiocarbamate (DDC). Exp Toxicol Pathol 2003 November;55(4):251-6.
58. Li JJ, Oberley LW. Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and/or hyperthermia. Cancer Res 1997 May 15;57(10):1991-8.
59. Lord-Fontaine S, Averill DA. Enhancement of cytotoxicity of hydrogen peroxide by hyperthermia in chinese hamster ovary cells: role of antioxidant defenses. Arch Biochem Biophys 1999 March 15;363(2):283-95.
60. Razavi R, Harrison LE. Thermal sensitization using induced oxidative stress decreases tumor growth in an in vivo model of hyperthermic intraperitoneal perfusion. Ann Surg Oncol 2010 January;17(1):304-11.
61. Blackman RK, Cheung-Ong K, Gebbia M et al. Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. PLoS ONE 2012;7(1):e29798.
62. Barbi de MM, Vincent G, Fayewicz SL et al. Mitochondrial respiration--an important therapeutic target in melanoma. PLoS ONE 2012;7(8):e40690.
63. Nagai M, Vo NH, Shin OL et al. The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells. Free Radic Biol Med 2012 May 15;52(10):2142-50.
64. Chen V, Staub RE, Baggett S et al. Identification and analysis of the active phytochemicals from the anti-cancer botanical extract Bezielle. PLoS ONE 2012;7(1):e30107.
65. Chen V, Staub RE, Fong S, Tagliaferri M, Cohen I, Shtivelman E. Bezielle selectively targets mitochondria of cancer cells to inhibit glycolysis and OXPHOS. PLoS ONE 2012;7(2):e30300.
66. Kluza J, Corazao-Rozas P, Touil Y et al. Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res 2012 October 1;72(19):5035-47.
67. O'Day SJ, Eggermont AM, Chiarion-Sileni V et al. Final results of phase III SYMMETRY study:randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol 2013 March 20;31(9):1211-8.
68. Ho J, de Moura MB, Lin Y et al. Importance of glycolysis and oxidative phosphorylation in advanced melanoma. Mol Cancer 2012;11:76.
69. Hasinoff BB, Yadav AA, Patel D, Wu X. The cytotoxicity of the anticancer drug elesclomol is due to oxidative stress indirectly mediated through its complex with Cu(II). J Inorg Biochem 2014 August;137:22-30.
70. Verrax J, Taper H, Buc CP. Targeting cancer cells by an oxidant-based therapy. Curr Mol Pharmacol 2008 January;1(1):80-92.
71. Verrax J, Stockis J, Tison A, Taper HS, Calderon PB. Oxidative stress by ascorbate/menadione association kills K562 human chronic myelogenous leukaemia cells and inhibits its tumour growth in nude mice. Biochem Pharmacol 2006 September 14;72(6):671-80.
72. Lai H, Nakase I, Lacoste E, Singh NP, Sasaki T. Artemisinin-transferrin conjugate retards growth of breast tumors in the rat. Anticancer Res 2009 October;29(10):3807-10.
73. Chan HW, Singh NP, Lai HC. Cytotoxicity of dihydroartemisinin toward Molt-4 cells attenuated by N-tert-butyl-alpha-phenylnitrone and deferoxamine. Anticancer Res 2013 October;33(10):4389-93.
74. Park J, Lai HC, Singh M, Sasaki T, Singh NP. Development of a Dihydroartemisinin-resistant Molt-4 Leukemia Cell Line. Anticancer Res 2014 June;34(6):2807-10.
75. Pinnix ZK, Miller LD, Wang W et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2010 August 4;2(43):43ra56.
76. Hann HW, Stahlhut MW, Blumberg BS. Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res 1988 August 1;48(15):4168-70.
77. Buss JL, Torti FM, Torti SV. The role of iron chelation in cancer therapy. Curr Med Chem 2003 June;10(12):1021-34.
78. Whitnall M, Howard J, Ponka P, Richardson DR. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA 2006 October 3;103(40):14901-6.
79. Miller LD, Coffman LG, Chou JW et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res 2011 November 1;71(21):6728-37.
80. Wu KJ, Polack A, Dalla-Favera R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science 1999 January 29;283(5402):676-9.
81. Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood 2002 May 15;99(10):3505-16.
82. O'Donnell KA, Yu D, Zeller KI et al. Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol Cell Biol 2006 March;26(6):2373-86.
83. Habel ME, Jung D. c-Myc over-expression in Ramos Burkitt's lymphoma cell line predisposes to iron homeostasis disruption in vitro. Biochem Biophys Res Commun 2006 March 24;341(4):1309-16.
84. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.Oncogene 2010 February 4;29(5):625-34.
85. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 2013 September 3;123(9):3664-71.
86. Rolfs A, Kvietikova I, Gassmann M, Wenger RH. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem 1997 August 8;272(32):20055-62.
87. Lok CN, Ponka P. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 1999 August 20;274(34):24147-52.
88. Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G. Transferrin receptor induction by hypoxia.HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem 1999 August 20;274(34):24142-6.
89. McCarty MF. Turning an 'Achilles' Heel' into an asset--activation of HIF-1alpha during angiostatic therapy will increase tumor sensitivity to iron-catalyzed oxidative damage. Med Hypotheses 2003 October;61(4):509-11.
90. Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem 1995 June 23;270(25):15285-93.
91. Pham CG, Bubici C, Zazzeroni F et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 2004 November 12;119(4):529-42.
92. Kiessling MK, Klemke CD, Kaminski MM, Galani IE, Krammer PH, Gulow K. Inhibition of constitutively activated nuclear factor-kappaB induces reactive oxygen species- and irondependent cell death in cutaneous T-cell lymphoma. Cancer Res 2009 March 15;69(6):2365-74.
93. Bakker GR, Boyer RF. Iron incorporation into apoferritin. The role of apoferritin as a ferroxidase.J Biol Chem 1986 October 5;261(28):13182-5.
94. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998 November 5;396(6706):77-80.
95. McCarty MF, Block KI. Preadministration of high-dose salicylates, suppressors of NF-kappaBactivation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy. Integr Cancer Ther 2006 September;5(3):252-68.
96. Wickerath M, Singh NP. Additive cytotoxic effects of dihydroartemisinin and sodium salicylate on cancer cells. Anticancer Res 2014 July;34(7):3399-401.
97. Singh NP, Lai HC. Artemisinin induces apoptosis in human cancer cells. Anticancer Res 2004 July;24(4):2277-80.
98. Scheiman JM, Elta GH. Gastroduodenal mucosal damage with salsalate versus aspirin: results of experimental models and endoscopic studies in humans. Semin Arthritis Rheum 1990 October;20(2):121-7.
99. McCarty MF. Salsalate may have broad utility in the prevention and treatment of vascular disorders and the metabolic syndrome. Med Hypotheses 2010 September;75(3):276-81.
100. Bombardier C, Peloso PM, Goldsmith CH. Salsalate, a nonacetylated salicylate, is as efficacious as diclofenac in patients with rheumatoid arthritis. Salsalate-Diclofenac Study Group. J Rheumatol 1995 April;22(4):617-24.
101. Moore JC, Lai H, Li JR et al. Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett 1995 November 27;98(1):83-7.
102. Singh NP, Lai H. Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci 2001 November 21;70(1):49-56.
103. Keeler B, Simpson J, Ng S et al. The feasibility and clinical efficacy of intravenous iron administration for preoperative anaemia in patients with colorectal cancer. Colorectal Dis 2014 June 10.
104. Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation,and disease. FASEB J 2003 July;17(10):1195-214.
105. Storr SJ, Woolston CM, Zhang Y, Martin SG. Redox environment, free radical, and oxidative DNA damage. Antioxid Redox Signal 2013 June 20;18(18):2399-408.
106. Huber A, Bai P, de Murcia JM, de MG. PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair (Amst) 2004 August;3(8-9):1103-8.
107. Yamamoto N, Nokihara H, Yamada Y et al. A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci 2012 March;103(3):504-9.
108. Bundred N, Gardovskis J, Jaskiewicz J et al. Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery. Invest New Drugs 2013 August;31(4):949-58.
109. Ma 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 February 5;6(222):222ra18.
110. Samol J, Ranson M, Scott E et al. Safety and tolerability of the poly(ADP-ribose) polymerase(PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment ofpatients with advanced solid tumors: a phase I study. Invest New Drugs 2012 August;30(4):1493-500.
111. Rajan A, Carter CA, Kelly RJ et al. A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res 2012 April 15;18(8):2344-51.
112. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012 April 12;366(15):1382-92.
113. Dent RA, Lindeman GJ, Clemons M et al. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triplenegative breast cancer. Breast Cancer Res 2013;15(5):R88.
114. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinumsensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014 July;15(8):852-61.
115. Riordan HD, Riordan NH, Jackson JA et al. Intravenous vitamin C as a chemotherapy agent: areport on clinical cases. P R Health Sci J 2004 June;23(2):115-8.
116. Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 2006 March 28;174(7):937-42.
117. Chen Q, Espey MG, Sun AY et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 2008 August 12;105(32):11105-9.
118. Stephenson CM, Levin RD, Spector T, Lis CG. 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 July;72(1):139-46.
119. Espey MG, Chen P, Chalmers B et al. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med 2011 June 1;50(11):1610-9.
120. Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med 2009 July 1;47(1):32-40.
121. Welsh JL, Wagner BA, van't Erve TJ 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 March;71(3):765-75.
122. Ma 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 February 5;6(222):222ra18.
123. McCarty MF, Barroso-Aranda J, Contreras F. Oxidative stress therapy for solid tumors - aproposal. Med Hypotheses 2010 June;74(6):1052-4.
124. Cui X. Reactive oxygen species: the achilles' heel of cancer cells? Antioxid Redox Signal 2012 June 1;16(11):1212-4.
125. Kuiper C, Dachs GU, Munn D et al. Increased Tumor Ascorbate is Associated with Extended Disease-Free Survival and Decreased Hypoxia-Inducible Factor-1 Activation in Human Colorectal Cancer. Front Oncol 2014;4:10.
126. Kuiper C, Molenaar IG, Dachs GU, Currie MJ, Sykes PH, Vissers MC. Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res 2010 July 15;70(14):5749-58.
127. Kuiper C, Dachs GU, Currie MJ, Vissers MC. Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free Radic Biol Med 2014 April;69:308-17.
128. Vissers MC, Gunningham SP, Morrison MJ, Dachs GU, Currie MJ. Modulation of hypoxiainducible factor-1 alpha in cultured primary cells by intracellular ascorbate. Free Radic Biol Med 2007 March 15;42(6):765-72.
129. McCarty MF. Expression and/or activity of the SVCT2 ascorbate transporter may be decreased in many aggressive cancers, suggesting potential utility for sodium bicarbonate and dehydroascorbic acid in cancer therapy. Med Hypotheses 2013 October;81(4):664-70.
130. Parrow NL, Leshin JA, Levine M. Parenteral ascorbate as a cancer therapeutic: a reassessment based on pharmacokinetics. Antioxid Redox Signal 2013 December 10;19(17):2141-56.