This research program will the investigate use of pharmacologic ascorbate (high-dose, i.v. delivery of vitamin C) in the treatment of cancer. Pharmacological ascorbate (AscH-) takes advantage of the basic chemical properties of AscH- to use it as a drug;in fact because of its properties as a reducing agent, pharmacologic AscH- is a pro-drug for the delivery of extracellular H2O2 to tumor cells. In this use of AscH-, it must be given intravenously;plasma levels of 20 - 30 mM are achieved;healthy individuals have plasma ascorbate levels on the order of 50 ?M (0.05 mM). With pharmacological AscH- the goal is to achieve a transient level of ascorbate in plasma on the order of 300-500 times that of typical healthy """"""""nutritional"""""""" levels. The half-life of AscH- in plasma at these high levels is H2.3 h. Thus for 12 - 24 h after treatment, levels of AscH- in plasma greatly exceed healthy """"""""nutritional"""""""" levels. We propose to investigate the mechanism of action of pharmacological AscH- to learn: (1) what biochemical properties make cancer cells susceptible to pharmacological AscH-;and (2) why it is not toxic to normal tissue. Our goal is to unravel basic biochemical mechanisms so this therapy can be employed in a broad range of appropriately selected cancers. We hypothesize that the difference in susceptibility of cells to pharmacological AscH- is the ability o maintain their intracellular redox buffer (GSSG,2H+/2GSH) at a half-cell reduction potential (Ehc) compatible with life. The rationale for this hypothesis is that: (1) AscH- readily autoxidize producing a flux of H2O2 (in cell culture media and in vivo);(2) the high levels of extra cellular AscH- achieved by i.v. delivery (H300-500X """"""""nutritional"""""""" levels) produce a high flux of H2O2;(3) the removal of this high flux of H2O2 by cells results in a great demand for intracellular reducing equivalents, i.e. glutathione (GSH) and NADPH;(4) this results in oxidation of the intracellular redox buffer, leading to quiescence or cell death, depending on the extent of oxidation. Cells that maintain an appropriately reduced intracellular redox buffer will be less susceptible to exposure to pharmacological AscH-;cells that cannot maintain their intracellular redox buffer will die. Because the status of the redox buffer is maintained by the pentose phosphate pathway (PPP), we further propose that an oxidatively challenged redox buffer will be synergistic with agents that also connect to the PPP, e.g. gemcitabine, 5-fluorouricil, and especially ionizing radiation. This research program supports translational efforts by addressing the fundamental question of why pharmacological ascorbate is non-toxic to organisms, i.e. people, yet cancer cells can be very susceptible. The results of this study will guide translational efforts in selectng appropriate adjuvants for therapy and cancers (patients) that may benefit from this approach to treatment. 2

Public Health Relevance

This proposal supports translational efforts to use pharmacologic ascorbate (high-dose, i.v. delivery of vitamin C) in the treatment of cancer. It addresses the fundamental question of why pharmacological ascorbate elicits a range of responses from cancer cells. The results of this study will guide translational efforts in selectin appropriate adjuvants for this therapy and selecting cancers (patients) that may benefit from this approach to treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Forry, Suzanne L
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University of Iowa
Schools of Medicine
Iowa City
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Wilkes, Justin G; O'Leary, Brianne R; Du, Juan et al. (2018) Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1? (HIF-1?) in pancreatic adenocarcinoma. Clin Exp Metastasis 35:37-51
Erudaitius, Dieanira; Mantooth, Jacqueline; Huang, Andrew et al. (2018) Calculated cell-specific intracellular hydrogen peroxide concentration: Relevance in cancer cell susceptibility during ascorbate therapy. Free Radic Biol Med 120:356-367
Schoenfeld, Joshua D; Sibenaller, Zita A; Mapuskar, Kranti A et al. (2018) Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models. Redox Biol 14:417-422
Brandt, Kristin E; Falls, Kelly C; Schoenfeld, Joshua D et al. (2018) Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells. Redox Biol 14:82-87
Alexander, Matthew S; Wilkes, Justin G; Schroeder, Samuel R et al. (2018) Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer. Cancer Res 78:6838-6851
Schoenfeld, Joshua D; Sibenaller, Zita A; Mapuskar, Kranti A et al. (2017) O2?- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell 31:487-500.e8
Erudaitius, Dieanira; Huang, Andrew; Kazmi, Sarah et al. (2017) Peroxiporin Expression Is an Important Factor for Cancer Cell Susceptibility to Therapeutic H2O2: Implications for Pharmacological Ascorbate Therapy. PLoS One 12:e0170442
Witmer, Jordan R; Wetherell, Bailey J; Wagner, Brett A et al. (2016) Direct spectrophotometric measurement of supra-physiological levels of ascorbate in plasma. Redox Biol 8:298-304
Cieslak, John A; Sibenaller, Zita A; Walsh, Susan A et al. (2016) Fluorine-18-Labeled Thymidine Positron Emission Tomography (FLT-PET) as an Index of Cell Proliferation after Pharmacological Ascorbate-Based Therapy. Radiat Res 185:31-8
Wangpradit, Orarat; Rahaman, Asif; Mariappan, S V Santhana et al. (2016) Breaking the dogma: PCB-derived semiquinone free radicals do not form covalent adducts with DNA, GSH, and amino acids. Environ Sci Pollut Res Int 23:2138-47

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