Assessment of Tumor Redox Status through (<i>S</i>)-4-(3-[¹⁸F]fluoropropyl)-L-Glutamic Acid PET Imaging of System x_c ^- Activity.

Abstract

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system x_c ^- 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 x_c ^--specific PET radiotracer, (<i>S</i>)-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 <i>de novo</i> glutathione biosynthesis, shown through [U-¹³C₆, U-¹⁵N₂]cystine isotopic tracing. <i>In vivo</i>, 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. SIGNIFICANCE: [¹⁸F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy.<i>See related commentary by Lee et al., p. 701</i>.