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
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
November-2017 Volume 16 Issue 5

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
November-2017 Volume 16 Issue 5

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 Open Access

N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells

  • Authors:
    • Yuyong Liu
    • Ke Liu
    • Nian Wang
    • Huali Zhang
  • View Affiliations / Copyright

    Affiliations: Beijing Institute of Heart, Lung and Blood Vessel Disease, Capital Medical University Affiliated to Beijing Anzhen Hospital, Beijing 100029, P.R. China, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China
    Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 6626-6633
    |
    Published online on: September 8, 2017
       https://doi.org/10.3892/mmr.2017.7442
  • 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

N‑acetylcysteine (NAC), a precursor of glutathione, is a widely used thiol‑containing antioxidant and modulator of the intracellular redox state. Our previous study demonstrated that excess reduced glutathione (GSH) from NAC treatment paradoxically led to a reduction in glutathione redox potential, increased mitochondrial oxidation and caused cytotoxicity at lower reactive oxygen species levels in H9c2 cells. However, no detailed data are available on the molecular mechanisms of NAC‑induced cytotoxicity on H9c2 cells. In the present study, it was demonstrated that NAC‑induced cytotoxicity towards H9c2 cells was associated with apoptosis. The activation of caspase‑9 and ‑3, and cleavage of procaspase‑9 and ‑3, but not of caspase‑8, were involved in NAC‑induced apoptosis. The dissipation of mitochondrial transmembrane potential, release of cytochrome c, translocation of B cell lymphoma‑2 (Bcl‑2)‑associated X protein (Bax) to the mitochondria, and the increased ratio of Bax/Bcl‑2 mRNA indicated that NAC treatment‑induced apoptosis occurred mainly through the mitochondria‑dependent pathway. Redox western blot analysis demonstrated that NAC did not disrupt the highly oxidized environment of the endoplasmic reticulum, which was indicated by maintenance of the oxidized form of protein disulfide isomerase, an essential chaperone in the formation of disulfide bond formation in the endoplasmic reticulum. In addition, no significant changes in the expression of binding immunoglobulin protein or C/EBP homologous protein were apparent in the process of NAC‑induced apoptosis. Taken together, the present study demonstrated for the first time, to the best of our knowledge, that NAC induced apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells, and the exogenous GSH from NAC did not alter the oxidized milieu of the endoplasmic reticulum.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Hansen JM, Go YM and Jones DP: Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev Pharmacol Toxicol. 46:215–234. 2006. View Article : Google Scholar : PubMed/NCBI

2 

Harris C and Hansen JM: Oxidative stress, thiols and redox profiles. Methods Mol Biol. 889:325–346. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Schafer FQ and Buettner GR: Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 30:1191–1212. 2001. View Article : Google Scholar : PubMed/NCBI

4 

Trotter EW and Grant CM: Thioredoxins are required for protection against a reductive stress in the yeast Saccharomyces cerevisiae. Mol Microbiol. 46:869–878. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Rajasekaran NS, Connell P, Christians ES, Yan LJ, Taylor RP, Orosz A, Zhang XQ, Stevenson TJ, Peshock RM, Leopold JA, et al: Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell. 130:427–439. 2007. View Article : Google Scholar : PubMed/NCBI

6 

Rand JD and Grant CM: The thioredoxin system protects ribosomes against stress-induced aggregation. Mol Biol Cell. 17:387–401. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Mayer M and Noble M: N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proc Natl Acad Sci USA. 91:7496–7500. 1994; View Article : Google Scholar : PubMed/NCBI

8 

Park SA, Choi KS, Bang JH, Huh K and Kim SU: Cisplatin-induced apoptotic cell death in mouse hybrid neurons is blocked by antioxidants through suppression of cisplatin-mediated accumulation of p53 but not of Fas/Fas ligand. J Neurochem. 75:946–953. 2000. View Article : Google Scholar : PubMed/NCBI

9 

Rakshit S, Bagchi J, Mandal L, Paul K, Ganguly D, Bhattacharjee S, Ghosh M, Biswas N, Chaudhuri U and Bandyopadhyay S: N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide. Apoptosis. 14:298–308. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Wu MS, Lien GS, Shen SC, Yang LY and Chen YC: N-acetyl-L-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells. Mol Carcinog. 53 Suppl 1:E119–E129. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Qanungo S, Wang M and Nieminen AL: N-Acetyl-L-cysteine enhances apoptosis through inhibition of nuclear factor-kappaB in hypoxic murine embryonic fibroblasts. J Biol Chem. 279:50455–50464. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Zhang H, Limphong P, Pieper J, Liu Q, Rodesch CK, Christians E and Benjamin IJ: Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity. FASEB. 26:1442–1451. 2012. View Article : Google Scholar

13 

Lowry OH, Rosebrough NJ, Farr AL and Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem. 193:265–275. 1951.PubMed/NCBI

14 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

15 

Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Kuznetsov AV, Margreiter R, Amberger A, Saks V and Grimm M: Changes in mitochondrial redox state, membrane potential and calcium precede mitochondrial dysfunction in doxorubicin-induced cell death. Biochim Biophys Acta. 1813:1144–1152. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Sharpe JC, Arnoult D and Youle RJ: Control of mitochondrial permeability by Bcl-2 family members. Biochim Biophys Acta. 1644:107–113. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Mezghrani A, Fassio A, Benham A, Simmen T, Braakman I and Sitia R: Manipulation of oxidative protein folding and PDI redox state in mammalian cells. EMBO J. 20:6288–6296. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Morishima N, Nakanishi K, Takenouchi H, Shibata T and Yasuhiko Y: An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem. 277:34287–34294. 2002. View Article : Google Scholar : PubMed/NCBI

20 

Dodd S, Dean O, Copolov DL, Malhi GS and Berk M: N-acetylcysteine for antioxidant therapy: Pharmacology and clinical utility. Expert Opin Biol Ther. 8:1955–1962. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Dean O, Giorlando F and Berk M: N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 36:78–86. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Aruoma OI, Halliwell B, Hoey BM and Butler J: The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 6:593–597. 1989. View Article : Google Scholar : PubMed/NCBI

23 

Tsai JC, Jain M, Hsieh CM, Lee WS, Yoshizumi M, Patterson C, Perrella MA, Cooke C, Wang H, Haber E, et al: Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells. J Biol Chem. 271:3667–3670. 1996. View Article : Google Scholar : PubMed/NCBI

24 

Kolossov VL, Beaudoin JN, Ponnuraj N, DiLiberto SJ, Hanafin WP, Kenis PJ and Gaskins HR: Thiol-based antioxidants elicit mitochondrial oxidation via respiratory complex III. Am J Physiol Cell Physiol. 309:C81–C91. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Singh F, Charles AL, Schlagowski AI, Bouitbir J, Bonifacio A, Piquard F, Krähenbühl S, Geny B and Zoll J: Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis. Biochim Biophys Acta. 1853:1574–1585. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Hwang C, Sinskey AJ and Lodish HF: Oxidized redox state of glutathione in the endoplasmic reticulum. Science. 257:1496–1502. 1992. View Article : Google Scholar : PubMed/NCBI

27 

Guan D, Xu Y, Yang M, Wang H, Wang X and Shen Z: N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway. Mol Carcinog. 49:68–74. 2010.PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Liu Y, Liu K, Wang N and Zhang H: N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells. Mol Med Rep 16: 6626-6633, 2017.
APA
Liu, Y., Liu, K., Wang, N., & Zhang, H. (2017). N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells. Molecular Medicine Reports, 16, 6626-6633. https://doi.org/10.3892/mmr.2017.7442
MLA
Liu, Y., Liu, K., Wang, N., Zhang, H."N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells". Molecular Medicine Reports 16.5 (2017): 6626-6633.
Chicago
Liu, Y., Liu, K., Wang, N., Zhang, H."N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells". Molecular Medicine Reports 16, no. 5 (2017): 6626-6633. https://doi.org/10.3892/mmr.2017.7442
Copy and paste a formatted citation
x
Spandidos Publications style
Liu Y, Liu K, Wang N and Zhang H: N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells. Mol Med Rep 16: 6626-6633, 2017.
APA
Liu, Y., Liu, K., Wang, N., & Zhang, H. (2017). N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells. Molecular Medicine Reports, 16, 6626-6633. https://doi.org/10.3892/mmr.2017.7442
MLA
Liu, Y., Liu, K., Wang, N., Zhang, H."N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells". Molecular Medicine Reports 16.5 (2017): 6626-6633.
Chicago
Liu, Y., Liu, K., Wang, N., Zhang, H."N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells". Molecular Medicine Reports 16, no. 5 (2017): 6626-6633. https://doi.org/10.3892/mmr.2017.7442
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