Non-invasive Use of Positron Emission Tomography to Monitor Diethyl maleate and Radiation-Induced Changes in System xC− Activity in Breast Cancer
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The system xC− 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 xC−. 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.
[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 xC−). System xC− 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.
[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.
[18F]FASu is a specific system xC− PET radiotracer and as such it can be used to monitor system xC− 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.
Key wordsOxidative stress FASu Positron emission tomography Breast cancer Cystine transporter Glutathione Radiation therapy
We thank The British Columbia Cancer Research Centre Bénard laboratory staff, Iulia Dude, Dr. Jutta Zeisler, and Dr. Carlos Uribe, and Sorenson laboratory post-doctoral fellow Dr. Bo Rafn, for their technical help. We also thank Drs. Donald Yapp, Krista Chung, Nelson Wong, and Youssef Ben Bouchta for their assistance during tumor radiation therapy experiment on the SARRP machine.
This work was supported by funds from CIHR (201403COP, 329895) and NSERC CREATE IsoSiM Stipend, grant no. 448110, competition year 2014. TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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