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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA169046-01A1
Application #
8503948
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Forry, Suzanne L
Project Start
2013-05-07
Project End
2018-04-30
Budget Start
2013-05-07
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$313,325
Indirect Cost
$105,825
Name
University of Iowa
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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
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
Doskey, Claire M; Buranasudja, Visarut; Wagner, Brett A et al. (2016) Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy. Redox Biol 10:274-284
Xiao, Wusheng; Sarsour, Ehab H; Wagner, Brett A et al. (2016) Succinate dehydrogenase activity regulates PCB3-quinone-induced metabolic oxidative stress and toxicity in HaCaT human keratinocytes. Arch Toxicol 90:319-32
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
Du, Juan; Cieslak 3rd, John A; Welsh, Jessemae L et al. (2015) Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. Cancer Res 75:3314-26
Doskey, Claire M; van 't Erve, Thomas J; Wagner, Brett A et al. (2015) Moles of a Substance per Cell Is a Highly Informative Dosing Metric in Cell Culture. PLoS One 10:e0132572
Du, Juan; Wagner, Brett A; Buettner, Garry R et al. (2015) Role of labile iron in the toxicity of pharmacological ascorbate. Free Radic Biol Med 84:289-95
O'Leary, Brianne R; Fath, Melissa A; Bellizzi, Andrew M et al. (2015) Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 21:1741-51
Zhao, Hongxia; Jiang, Jingqiu; Wang, Yanli et al. (2015) Monohydroxylated Polybrominated Diphenyl Ethers (OH-PBDEs) and Dihydroxylated Polybrominated Biphenyls (Di-OH-PBBs): Novel Photoproducts of 2,6-Dibromophenol. Environ Sci Technol 49:14120-8

Showing the most recent 10 out of 26 publications