title: 18F-5-Fluoroaminosuberic Acid as a Potential Tracer to Gauge Oxidative Stress in Breast Cancer Models.
abstract: The cystine transporter (system xC-) is an antiporter of cystine and glutamate. It has relatively low basal expression in most tissues and becomes upregulated in cells under oxidative stress (OS) as one of the genes expressed in response to the antioxidant response element promoter. We have developed18F-5-fluoroaminosuberic acid (FASu), a PET tracer that targets system xC-The goal of this study was to evaluate18F-FASu as a specific gauge for system xC-activity in vivo and its potential for breast cancer imaging.Methods:18F-FASu specificity toward system xC-was studied by cell inhibition assay, cellular uptake after OS induction with diethyl maleate, with and without anti-xCT small interfering RNA knockdown, in vitro uptake studies, and in vivo uptake in a system xC--transduced xenograft model. In addition, radiotracer uptake was evaluated in 3 breast cancer models: MDA-MB-231, MCF-7, and ZR-75-1.Results:Reactive oxygen species-inducing diethyl maleate increased glutathione levels and18F-FASu uptake, whereas gene knockdown with anti-xCT small interfering RNA led to decreased tracer uptake.18F-FASu uptake was robustly inhibited by system xC-inhibitors or substrates, whereas uptake was significantly higher in transduced cells and tumors expressing xCT than in wild-type HEK293T cells and tumors (P< 0.0001 for cells,P= 0.0086 for tumors).18F-FASu demonstrated tumor uptake in all 3 breast cancer cell lines studied. Among them, triple-negative breast cancer MDA-MB-231, which has the highest xCT messenger RNA level, had the highest tracer uptake (P= 0.0058 when compared with MCF-7;P< 0.0001 when compared with ZR-75-1).Conclusion:18F-FASu as a system xC-substrate is a specific PET tracer for functional monitoring of system xC-and OS imaging. By enabling noninvasive analysis of xC-responses in vivo, this biomarker may serve as a valuable target for the diagnosis and treatment monitoring of certain breast cancers.
authors: Life Sciences, TRIUMF, Vancouver, Canada.
authors: Hua
authors: H
authors: Yang
authors: British Columbia Cancer Agency, Vancouver, Canada.
authors: Silvia
authors: S
authors: Jenni
authors: Life Sciences, TRIUMF, Vancouver, Canada.|Department of Radiology, University of British Columbia, Vancouver, Canada.
authors: Milena
authors: M
authors: Colovic
authors: British Columbia Cancer Agency, Vancouver, Canada.
authors: Helen
authors: H
authors: Merkens
authors: Life Sciences, TRIUMF, Vancouver, Canada.
authors: Carlee
authors: C
authors: Poleschuk
authors: Life Sciences, TRIUMF, Vancouver, Canada.
authors: Isabel
authors: I
authors: Rodrigo
authors: Life Sciences, TRIUMF, Vancouver, Canada.
authors: Qing
authors: Q
authors: Miao
authors: GE Global Research, Niskayuna, New York.
authors: Bruce F
authors: BF
authors: Johnson
authors: GE Global Research, Niskayuna, New York.
authors: Michael J
authors: MJ
authors: Rishel
authors: Department of Physics and Astronomy, University of British Columbia, Vancouver, Canada; and.
authors: Vesna
authors: V
authors: Sossi
authors: GE Global Research, Niskayuna, New York.
authors: Jack M
authors: JM
authors: Webster
authors: British Columbia Cancer Agency, Vancouver, Canada.|Department of Radiology, University of British Columbia, Vancouver, Canada.
authors: François
authors: F
authors: Bénard
authors: Life Sciences, TRIUMF, Vancouver, Canada pschaffer@triumf.ca.|Department of Radiology, University of British Columbia, Vancouver, Canada.|Department of Chemistry, Simon Fraser University, Vancouver, Canada.
authors: Paul
authors: P
authors: Schaffer
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000600:Amino Acids, Dicarboxylic / Q000493:pharmacokinetics*; D000975:Antioxidants / Q000378:metabolism; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D005240:Feasibility Studies; D006801:Humans; D018384:Oxidative Stress; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: C000588667:5-fluoroaminosuberic acid; D027182:Amino Acid Transport System y+; D000600:Amino Acids, Dicarboxylic; D000975:Antioxidants; D019275:Radiopharmaceuticals; C118895:SLC7A11 protein, human
keywords: F-18; PET; oxidative stress; system xC−; tumor imaging