Glutathione is a ubiquitous tripeptide found in high concentration in normal tissue and is frequently elevated in tumors. Glutathione and its oxidized disulfide form the primary reduction/oxidation (redox) buffer in the cell. The cellular redox balance controls gene expression, differentiation, proliferation and apoptosis. In normal tissue, glutathione protects the cell from environmental stress and the cancer cell has adapted this defense mechanism to shield tumor cells from the effects of therapy. In cell culture, our laboratory has shown that glutathione metabolism is consistently increased in drug-resistant cancers. These findings are supported by a number of clinical studies relating glutathione metabolism to patient survival. However the clinical studies rely upon invasive repeated sampling of the tumor tissue since methods to monitor glutathione metabolism in intact rumors are lacking. Over the past two years, as part of an NTH-funded pilot project, we succeeded in developing a magnetic resonance method combined with stable isotope infusion to monitor glutathione metabolism in vivo. This proposal builds upon the feasibility established in the pilot project and plans to Use these methods to monitor glutathione metabolism non-invasively in R3230 mammary, 9L glioma and FSA fibrosarcoma tumors and drug-resistant variants in rats. Glutathione metabolism will be assessed in relation to tumor growth rate, vascularization and expression of key enzymes involved in redox metabolism. Since a drop in intracellular glutathione levels is one of the earliest events in apoptosis, therapy-induced changes in glutathione metabolism detected by magnetic resonance will be an early indicator of tumor response. Since altered redox balance appears to be a universal characteristic of proliferating cells in general and cancer in particular, methods to non-invasively monitor redox metabolism offers new insight into a process critical to planning and evaluating cancer therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Zhang, Huiming
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
North Carolina State University Raleigh
Engineering (All Types)
Schools of Engineering
United States
Zip Code
Skamarauskas, John T; Oakley, Fiona; Smith, Fiona E et al. (2014) Noninvasive in vivo magnetic resonance measures of glutathione synthesis in human and rat liver as an oxidative stress biomarker. Hepatology 59:2321-30
Jeffries, Rex E; Gamcsik, Michael P; Keshari, Kayvan R et al. (2013) Effect of oxygen concentration on viability and metabolism in a fluidized-bed bioartificial liver using ³¹P and ¹³C NMR spectroscopy. Tissue Eng Part C Methods 19:93-100
Gamcsik, Michael P; Kasibhatla, Mohit S; Teeter, Stephanie D et al. (2012) Glutathione levels in human tumors. Biomarkers 17:671-91
Johnson, C Bryce; Tikunov, Andrey P; Lee, Haakil et al. (2012) ¹³C magnetic resonance spectroscopy detection of changes in serine isotopomers reflects changes in mitochondrial redox status. Magn Reson Med 68:671-9
Thelwall, Peter E; Simpson, Nicholas E; Rabbani, Zahid N et al. (2012) In vivo MR studies of glycine and glutathione metabolism in a rat mammary tumor. NMR Biomed 25:271-8
Seagle, Christopher; Christie, Megan A; Winnike, Jason H et al. (2008) High-throughput nuclear magnetic resonance metabolomic footprinting for tissue engineering. Tissue Eng Part C Methods 14:107-18
Turner, William S; Seagle, Chris; Galanko, Joseph A et al. (2008) Nuclear magnetic resonance metabolomic footprinting of human hepatic stem cells and hepatoblasts cultured in hyaluronan-matrix hydrogels. Stem Cells 26:1547-55