Assessing Oxidative Stress in Tumors by Measuring the Rate of Hyperpolarized [1-$^{13}$C] Dehydroascorbic Acid Reduction Using $^{13}$C Magnetic Resonance Spectroscopy
| Autor: | Timm, KN, Hu, D-E, Williams, M, Wright, AJ, Kettunen, MI, Kennedy, BWC, Larkin, TJ, Dzien, P, Marco-Rius, I, Bohndiek, SE, Brindle, KM |
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| Přispěvatelé: | Wright, Alan [0000-0002-4577-5681], Bohndiek, Sarah [0000-0003-0371-8635], Brindle, Kevin [0000-0003-3883-6287], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Carbon Isotopes
Magnetic Resonance Spectroscopy dehydroascorbic acid food and beverages Mice pentose phosphate pathway (PPP) Metabolism Cell Line Tumor Isotope Labeling Neoplasms Animals Humans oxidative stress tumor metabolism in vivo imaging glutathione glutathione peroxidase 13C NADP hyperpolarization |
| Zdroj: | The Journal of Biological Chemistry |
| Popis: | Rapid cancer cell proliferation promotes the production of reducing equivalents, which counteract the effects of relatively high levels of reactive oxygen species (ROS). ROS levels increase in response to chemotherapy and cell death while an increase in antioxidant capacity can confer resistance to chemotherapy and is associated with an aggressive tumor phenotype. The pentose phosphate pathway (PPP) is a major site of NADPH production in the cell, which is used to maintain the main intracellular antioxidant, glutathione, in its reduced state. Previous studies have shown that the rate of hyperpolarized [1-$^{13}$C]dehydroascorbic acid (DHA) reduction, which can be measured $\textit{in vivo}$ using non-invasive $^{13}$C magnetic resonance spectroscopic imaging, is increased in tumors and that this is correlated with the levels of reduced glutathione. We show here that the rate of hyperpolarized [1-$^{13}$C]DHA reduction is increased in tumors that have been oxidatively pre-stressed by depleting the glutathione pool by buthionine sulfoximine treatment. This increase was associated with a corresponding increase in PPP flux, assessed using $^{13}$C-labeled glucose, and an increase in glutaredoxin activity, which catalyzes the glutathione-dependent reduction of DHA. These results show that the rate of DHA reduction does not depend only on the level of reduced glutathione, but also on the rate of NADPH production, contradicting the conclusions of some previous studies. Hyperpolarized [1-$^{13}$C]DHA can be used therefore to assess the capacity of tumor cells to resist oxidative stress in vivo. However, DHA administration resulted in transient respiratory arrest and cardiac depression, which may prevent translation to the clinic. |
| Databáze: | OpenAIRE |
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