Assessment of tumor redox status through (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid positron emission tomography imaging of system xc- activity

McCormick, P. N. et al. (2019) Assessment of tumor redox status through (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid positron emission tomography imaging of system xc- activity. Cancer Research, 79(4), pp. 853-863. (doi:10.1158/0008-5472.CAN-18-2634) (PMID:30401715) (PMCID:PMC6379064)

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Abstract

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lewis, Dr David and Zhang, Mr Tong and Maddocks, Dr Oliver
Authors: McCormick, P. N., Greenwood, H. E., Glaser, M., Maddocks, O. D.K., Gendron, T., Sander, K., Gowrishankar, G., Hoehne, A., Zhang, T., Shuhendler, A. J., Lewis, D. Y., Berndt, M., Koglin, N., Lythgoe, M. F., Gambhir, S. S., Årstad, E., and Witney, T. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:06 November 2018
Copyright Holders:Copyright © 2018 American Association for Cancer Research
First Published:First published in Cancer Research 79(4): 853-863
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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