Non-invasive Use of Positron Emission Tomography to Monitor Diethyl maleate and Radiation-Induced Changes in System xC- Activity in Breast Cancer

Abstract

Purpose: The system x_C^- transporter is upregulated in cancer cells in response to oxidative stress (OS). 5-[¹⁸F]fluoroaminosuberic acid ([¹⁸F]FASu) has been reported as a novel positron emission tomography (PET) imaging agent, targeting system x_C^-. The goal of this study was to evaluate the utility of [¹⁸F]FASu in monitoring cellular response to diethyl maleate (DEM) and radiation-induced OS fluctuations.

Procedures: [¹⁸F]FASu uptake by breast cancer cells was studied in correlation to OS biomarkers: glutathione (GSH) and reactive oxygen species (ROS), as well as transcriptional and translational levels of xCT (the functional subunit of x_C^-). System x_C^- inhibitor, sulfasalazine (SSZ), and small interfering RNA (siRNA) knockdown were used as negative controls. Radiotracer uptake was evaluated in three breast cancer models: MDA-MB-231, MCF-7, and ZR-75-1, at two-time points (1 h and 16 h) following OS induction. In vivo [¹⁸F]FASu imaging and biodistribution were performed using MDA-MB-231 xenograft-bearing mice at 16 and 24 h post-radiation treatment.

Results: [¹⁸F]FASu uptake was positively correlated to intracellular GSH and SLC7A11 expression levels, and radiotracer uptake was induced both by radiation treatment and by DEM at time points longer than 3 h. In an in vivo setting, there was no statistically significant uptake difference between irradiated and control tumors.

Conclusion: [¹⁸F]FASu is a specific system x_C^- PET radiotracer and as such it can be used to monitor system x_C^- activity due to OS. As such, [¹⁸F]FASu has the potential to be used in therapy response monitoring by PET. Further optimization is required for in vivo application.

Keywords: Breast cancer; Cystine transporter; FASu; Glutathione; Oxidative stress; Positron emission tomography; Radiation therapy.