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Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 6/2019

01-12-2019 | Breast Cancer | Research Article

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

Authors: Milena Čolović, Hua Yang, Helen Merkens, Nadine Colpo, François Bénard, Paul Schaffer

Published in: Molecular Imaging and Biology | Issue 6/2019

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Abstract

Purpose

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.

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 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.

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 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.
Appendix
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Literature
1.
Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947CrossRef
2.
Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Cancer 11:85–95PubMed
3.
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRef
4.
Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL, Clarke MF (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458:780–783CrossRef
5.
Yang H, Jenni S, Čolović M et al (2017) 18F-5-fluoroaminosuberic acid as a potential tracer to gauge oxidative stress in breast cancer models. J Nucl Med 58:367–373CrossRef
6.
Ishii T, Sato H, Miura K et al (1992) Induction of cystine transport activity by stress. Ann N Y Acad Sci 663:497–498CrossRef
7.
Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Saeki S, Kanai Y, Endou H, Naito M, Tsuruo T, Terasaki T (2002) Enhancement of the L-cystine transport activity and its relation to xCT gene induction at the blood-brain barrier by diethyl maleate treatment. J Pharmacol Exp Ther 302:225–231CrossRef
8.
Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Maebara K, Wang H, Tamba M, Itoh K, Yamamoto M, Bannai S (2002) Electrophile response element – mediated introduction of the cystine/glutamate exchange transporter gene expression. J Biol Chem 277:44765–44771CrossRef
9.
Conrad M, Sato H (2012) The oxidative stress-inducible cystine/glutamate antiporter, system xc-: cystine supplier and beyond. Amino Acids 42:231–246CrossRef
10.
Bridges RJ, Natale NR, Patel SA (2012) System xc- cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 165:20–34CrossRef
11.
Smolarz K, Krause BJ, Graner FP, Wagner FM, Hultsch C, Bacher-Stier C, Sparks RB, Ramsay S, Fels LM, Dinkelborg LM, Schwaiger M (2013) (S)-4-(3-18F-Fluoropropyl)-L-glutamic acid: an 18F-labeled tumor-specific probe for PET/CT imaging--dosimetry. J Nucl Med 54:861–866CrossRef
12.
Koglin N, Mueller A, Berndt M, Schmitt-Willich H, Toschi L, Stephens AW, Gekeler V, Friebe M, Dinkelborg LM (2011) Specific PET imaging of xC − transporter activity using a 18F-labelled glutamate derivative reveals a dominant pathway in tumor metabolism. Clin Cancer Res 17:6000–6011CrossRef
13.
Gout PW, Buckley AR, Simms CR, Bruchovsky N (2001) Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc- cystine transporter: a new action for an old drug. Leukemia 15:1633–1640CrossRef
14.
Müerköster S, Arlt A, Witt M, Gehrz A, Haye S, March C, Grohmann F, Wegehenkel K, Kalthoff H, Fölsch UR, Schäfer H (2003) Usage of the NF-kappa B inhibitor sulfasalazine as sensitizing agent in combined chemotherapy of pancreatic cancer. Int J Cancer 104:469–476CrossRef
15.
Lay JD, Hong CC, Huang JS, Yang YY, Pao CY, Liu CH, Lai YP, Lai GM, Cheng AL, Su IJ, Chuang SE (2007) Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. Cancer Res 67:3878–3887CrossRef
16.
Narang VS, Pauletti GM, Gout PW, Buckley DJ, Buckley AR (2007) Sulfasalazine induced reduction of glutathione levels in breast cancer cells: enhancement of growth-inhibitory activity of doxorubicin. Chemotherapy 53:210–217CrossRef
17.
Pham AN, Blower PE, Alvarado O, Ravula R, Gout PW, Huang Y (2010) Pharmacogenomic approach reveals a role for the xc- cystine/glutamate antiporter in growth and celastrol resistance of glioma cell lines. J Pharmacol Exp Ther 332:949–958CrossRef
18.
Keam B, Im SA, Kim HJ (2007) Prognostic impact of clinicopathologic parameters in stage II/III breast cancer treated with neoadjuvant docetaxel and doxorubicin chemotherapy: paradoxical features of the triple negative breast cancer. BMC Cancer 7:203CrossRef
19.
Timmerman LA, Holton T, Yuneva M (2013) Glutamine sensitivity analysis indentifies the xCT antiporter as a common triple-negative breast tumour therapeutic target. Cancer Cell 24:450–465CrossRef
20.
Webster JM, Morton CA, Johnson BF, Yang H, Rishel MJ, Lee BD, Miao Q, Pabba C, Yapp DT, Schaffer P (2014) Functional imaging of oxidative stress with a novel PET imaging agent, 18F-5-fluoro-L-aminosuberic acid. J Nucl Med 55:657–664CrossRef
21.
Liefferinge JV, Bentea E, Demuyser T et al (2016) Comparative analysis of antibodies to xCT (SLC7A11): forewarned is forarmed. J Comp Neurol 524:1015–1032CrossRef
22.
Sato H, Tamba M, Ishii T, Bannai S (1999) Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem 274:11455–11458CrossRef
23.
Massie A, Schallier A, Mertens B, Vermoesen K, Bannai S, Sato H, Smolders I, Michotte Y (2008) Time-dependent changes in striatal xCT protein expression in hemi-Parkinson rats. Neuroreport 19:1589–1592CrossRef
24.
Burdo J, Dargusch R, Schubert D (2006) Distribution of the cystine/glutamate antiporter system X2c in the brain, kidney, and duodenum. J Histochem Cytochem 54:549–557CrossRef
25.
Shih AY, Erb H, Sun X, Toda S, Kalivas PW, Murphy TH (2006) Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. J Neurosci 26:10514–10523CrossRef
26.
La Bella V, Valentino F, Piccoli T, Piccoli F (2007) Expression and developmental regulation of the cystine/glutamate exchanger (X2c) in the rat. Neurochem Res 32:1081–1090CrossRef
Metadata
Title
Non-invasive Use of Positron Emission Tomography to Monitor Diethyl maleate and Radiation-Induced Changes in System xC− Activity in Breast Cancer
Authors
Milena Čolović
Hua Yang
Helen Merkens
Nadine Colpo
François Bénard
Paul Schaffer
Publication date
01-12-2019
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 6/2019
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-019-01331-8

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