Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Letters
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-1074 Online ISSN: 1792-1082
Journal Cover
June-2018 Volume 15 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
June-2018 Volume 15 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors

  • Authors:
    • Satoru Nishizawa
    • Hideo Araki
    • Yoshinori Ishikawa
    • Satoshi Kitazawa
    • Akito Hata
    • Tomoyoshi Soga
    • Takahito Hara
  • View Affiliations / Copyright

    Affiliations: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251‑8555, Japan, Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251‑8555, Japan, Institute for Advanced Bioscience, Keio University, Tsuruoka, Yamagata 997‑0052, Japan
  • Pages: 8735-8743
    |
    Published online on: April 10, 2018
       https://doi.org/10.3892/ol.2018.8447
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Previous metabolomic analyses of cancer have revealed elevated glutathione levels in tumors. An inhibitor of cystine uptake was identified to suppress glutathione biosynthesis, leading to ferroptosis, a novel iron‑dependent form of cell death that differs from apoptosis and necrosis. Glutamate‑cysteine ligase (GCL) is the rate‑limiting enzyme in the glutathione biosynthesis pathway. Buthionine sulfoximine (BSO), a GCL inhibitor, has previously demonstrated limited clinical benefits. Therefore, selecting patients who respond well to the inhibitor is a key approach for successful future drug development. Ferroptosis induction by BSO has not been fully examined in prior studies. Therefore, the present study investigated the pharmacological effects of BSO and the association between basal intracellular glutathione levels and sensitivity to BSO in cultured cell lines derived from various types of cancer, including those of the kidney [769P, 786‑O, A‑498, A704, ACHN, Caki‑1, Caki‑2, G401, G402, RCC4 VHL(‑/‑), RCC4 VHL(+/+), SK‑NEP‑1 and SW156] and ovaries (A2780 and A2780/CDDP). BSO was demonstrated to suppress glutathione levels and induce lipid peroxidation, thereby inhibiting cell viability. The viability‑reducing effects of BSO were attenuated by ferroptosis inhibition and enhanced by iron, indicating that BSO induced ferroptosis in cancer cells. The cell lines sensitive to BSO, including G402, tended to exhibit non‑significantly lower levels of glutathione compared with the BSO‑insensitive cell lines, including Caki‑2 (P=0.08). Patient sample data indicated the existence of a population of colorectal tumors with lower glutathione levels compared with those of matched normal tissues that might be suitable for the clinical testing of sensitivity to GCLC inhibitors. Collectively, these data suggest that GCL inhibition leads to ferroptosis in cancer cells, and that low glutathione tumor levels may be a patient selection marker for the use of GCL inhibitors in the treatment of tumors.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI

2 

Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Cairns RA, Harris IS and Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 11:85–95. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A, Aksoy BA, Liu EM, Shen R, Lee W, et al: An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell. 29:104–116. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Denkert C, Budczies J, Weichert W, Wohlgemuth G, Scholz M, Kind T, Niesporek S, Noske A, Buckendahl A, Dietel M and Fiehn O: Metabolite profiling of human colon carcinoma-deregulation of TCA cycle and amino acid turnover. Mol Cancer. 7:722008. View Article : Google Scholar : PubMed/NCBI

6 

Wang H, Wang L, Zhang H, Deng P, Chen J, Zhou B, Hu J, Zou J, Lu W, Xiang P, et al: ¹H NMR-based metabolic profiling of human rectal cancer tissue. Mol Cancer. 12:1212013. View Article : Google Scholar : PubMed/NCBI

7 

Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD, Mathew LK, Mancuso A, Gade TP, Keith B, Nissim I and Simon MC: Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature. 513:251–255. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156:317–331. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Yang WS and Stockwell BR: Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 26:165–176. 2016. View Article : Google Scholar : PubMed/NCBI

11 

Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg PA, Lo DC, Weinberg JM, Linkermann A and Stockwell BR: Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. 136:4551–4556. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R and Tang D: Ferroptosis: Process and function. Cell Death Differ. 23:369–379. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Lu SC: Glutathione synthesis. Biochim Biophys Acta. 1830:3143–3153. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Bailey HH, Ripple G, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Mahvi D, Schink J, Pomplun M, Mulcahy RT and Wilding G: Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst. 89:1789–1796. 1997. View Article : Google Scholar : PubMed/NCBI

15 

Sakamoto K, Adachi Y, Komoike Y, Kamada Y, Koyama R, Fukuda Y, Kadotani A, Asami T and Sakamoto JI: Novel DOCK2-selective inhibitory peptide that suppresses B-cell line migration. Biochem Biophys Res Commun. 483:183–190. 2017. View Article : Google Scholar : PubMed/NCBI

16 

Winterbourn CC and Brennan SO: Characterization of the oxidation products of the reaction between reduced glutathione and hypochlorous acid. Biochem J. 326:87–92. 1997. View Article : Google Scholar : PubMed/NCBI

17 

Winkler BS, DeSantis N and Solomon F: Multiple NADPH-producing pathways control glutathione (GSH) content in retina. Exp Eye Res. 43:829–847. 1986. View Article : Google Scholar : PubMed/NCBI

18 

Patra KC and Hay N: The pentose phosphate pathway and cancer. Trends Biochem Sci. 39:347–354. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Muñoz-Pinedo C, El Mjiyad N and Ricci JE: Cancer metabolism: Current perspectives and future directions. Cell Death Dis. 3:e2482012. View Article : Google Scholar : PubMed/NCBI

20 

Singh D, Arora R, Kaur P, Singh B, Mannan R and Arora S: Overexpression of hypoxia-inducible factor and metabolic pathways: Possible targets of cancer. Cell Biosci. 7:622017. View Article : Google Scholar : PubMed/NCBI

21 

Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM and Karagiannis TC: Cancer metabolism and the Warburg effect: The role of HIF-1 and PI3K. Mol Biol Rep. 42:841–851. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Haase VH: The VHL tumor suppressor: Master regulator of HIF. Curr Pharm Des. 15:3895–3903. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Satoh K, Yachida S, Sugimoto M, Oshima M, Nakagawa T, Akamoto S, Tabata S, Saitoh K, Kato K, Sato S, et al: Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC. Proc Natl Acad Sci USA. 114:E7697–E7706. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Yuan M, Breitkopf SB, Yang X and Asara JM: A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat Protoc. 7:872–881. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Soga T and Heiger DN: Amino acid analysis by capillary electrophoresis electrospray ionization mass spectrometry. Anal Chem. 72:1236–1241. 2000. View Article : Google Scholar : PubMed/NCBI

26 

Soga T, Ohashi Y, Ueno Y, Naraoka H, Tomita M and Nishioka T: Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J Proteome Res. 2:488–494. 2003. View Article : Google Scholar : PubMed/NCBI

27 

Soga T, Igarashi K, Ito C, Mizobuchi K, Zimmermann HP and Tomita M: Metabolomic profiling of anionic metabolites by capillary electrophoresis mass spectrometry. Anal Chem. 81:6165–6174. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Bailey HH, Mulcahy RT, Tutsch KD, Arzoomanian RZ, Alberti D, Tombes MB, Wilding G, Pomplun M and Spriggs DR: Phase I clinical trial of intravenous L-buthionine sulfoximine and melphalan: An attempt at modulation of glutathione. J Clin Oncol. 12:194–205. 1994. View Article : Google Scholar : PubMed/NCBI

29 

Mehta S, Shelling A, Muthukaruppan A, Lasham A, Blenkiron C, Laking G and Print C: Predictive and prognostic molecular markers for cancer medicine. Ther Adv Med Oncol. 2:125–148. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Dienstmann R, Rodon J and Tabernero J: Biomarker-driven patient selection for early clinical trials. Curr Opin Oncol. 25:305–312. 2013.PubMed/NCBI

31 

Schmidt KT, Chau CH, Price DK and Figg WD: Precision oncology medicine: The clinical relevance of patient-specific biomarkers used to optimize cancer treatment. J Clin Pharmacol. 56:1484–1499. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Terpstra M, Vaughan TJ, Ugurbil K, Lim KO, Schulz SC and Gruetter R: Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T: Application to schizophrenia. MAGMA. 18:276–282. 2005. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Nishizawa S, Araki H, Ishikawa Y, Kitazawa S, Hata A, Soga T and Hara T: Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors. Oncol Lett 15: 8735-8743, 2018.
APA
Nishizawa, S., Araki, H., Ishikawa, Y., Kitazawa, S., Hata, A., Soga, T., & Hara, T. (2018). Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors. Oncology Letters, 15, 8735-8743. https://doi.org/10.3892/ol.2018.8447
MLA
Nishizawa, S., Araki, H., Ishikawa, Y., Kitazawa, S., Hata, A., Soga, T., Hara, T."Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors". Oncology Letters 15.6 (2018): 8735-8743.
Chicago
Nishizawa, S., Araki, H., Ishikawa, Y., Kitazawa, S., Hata, A., Soga, T., Hara, T."Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors". Oncology Letters 15, no. 6 (2018): 8735-8743. https://doi.org/10.3892/ol.2018.8447
Copy and paste a formatted citation
x
Spandidos Publications style
Nishizawa S, Araki H, Ishikawa Y, Kitazawa S, Hata A, Soga T and Hara T: Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors. Oncol Lett 15: 8735-8743, 2018.
APA
Nishizawa, S., Araki, H., Ishikawa, Y., Kitazawa, S., Hata, A., Soga, T., & Hara, T. (2018). Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors. Oncology Letters, 15, 8735-8743. https://doi.org/10.3892/ol.2018.8447
MLA
Nishizawa, S., Araki, H., Ishikawa, Y., Kitazawa, S., Hata, A., Soga, T., Hara, T."Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors". Oncology Letters 15.6 (2018): 8735-8743.
Chicago
Nishizawa, S., Araki, H., Ishikawa, Y., Kitazawa, S., Hata, A., Soga, T., Hara, T."Low tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors". Oncology Letters 15, no. 6 (2018): 8735-8743. https://doi.org/10.3892/ol.2018.8447
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team