King＇s College London / Witney TH*
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.
McCormick PN1, Greenwood HE1, Glaser M2, Maddocks ODK3, Gendron T2, Sander K4, Gowrishankar G5, Hoehne A6, Zhang T7, Shuhendler AJ8, Lewis DY9, Berndt M10, Koglin N11, Lythgoe MF12, Gambhir SS5, Årstad E13, Witney TH14.
Division of Medicine, University College London.
Institute of Nuclear Medicine and Department of Chemistry, University College London.
Institute of Cancer Sciences, University of Glasgow.
Institute of Nuclear Medicine and Department of Chemistry, UCL.
Radiology, Stanford University.
Wolfson Wohl Cancer Research Centre, University of Glasgow.
Department of Radiology, Stanford University.
Molecular Imaging Group, Cancer Research UK Beatson Institute.
Radiochemistry, Life Molecular Imaging.
Life Molecular Imaging GmbH, Clinical Development.
Division of Medicine, Centre for Advanced Biomedical Imaging, University College London.
Chemistry and Institute of Nuclear Medicine, UCL.
Imaging Chemistry and Biology, King's College London firstname.lastname@example.org.