Skip to main content
SpringerLink
Log in

α-Hederin Induces Apoptosis of Esophageal Squamous Cell Carcinoma via an Oxidative and Mitochondrial-Dependent Pathway

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

α-Hederin has been shown promising anti-tumor potential against various cancer cell lines. However, reports about effects of α-hederin on esophageal squamous cell carcinoma (ESCC) are still unavailable.

Aim

To investigate the inhibitory effects of α-hederin on ESCC and explore the underlying mechanism.

Methods

Human esophageal carcinoma cell line (Eca-109) was used for the experiment. Cell Counting Kit-8, flow cytometry, Hoechst 33258 staining, enhanced ATP assay kit, 2′,7′-dichlorofluorescin diacetate, JC-1 kit, and Western bolt were used to assess the cell viability, cycle, apoptosis, cellular ATP content, reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and protein expression, respectively, in vitro. Xenografted tumor model was constructed to evaluate the in vivo anti-tumor effects of α-hederin.

Results

Compared with control group, α-hederin significantly inhibited the proliferation, induced apoptosis of ESCC, and arrested the cell cycle in G1 phase (P < 0.05). α-Hederin induced the accumulation of ROS, decrement of ATP levels, and disruption of MMP (P < 0.05). The detection of mitochondrial and cytosol proteins showed that AIF, Apaf-1, and Cyt C were released and increased in cytoplasm, and then, caspase-3, caspase-9, and Bax were involved and increased, while Bcl-2 level was decreased (P < 0.05). Furthermore, the above changes were amplified in the group pretreated with l-buthionine sulfoximine, while N-acetyl-l-cysteine plays an opposite role (P < 0.05). Meanwhile, α-hederin significantly inhibited the growth of xenografted tumors with favorable safety.

Conclusion

α-Hederin could inhibit the proliferation and induce apoptosis of ESCC via dissipation of the MMP with simultaneous ROS generation and activation of the mitochondrial pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA A Cancer J Clin. 2015;65:87–108.

    Article  Google Scholar 

  2. Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 2018;154:360–373.

    Article  Google Scholar 

  3. Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet. 2017;390:2383–2396.

    Article  Google Scholar 

  4. Haas SL, Ye W, Lohr JM. Alcohol consumption and digestive tract cancer. Curr Opin Clin Nutr Metab Care. 2012;15:457–467.

    Article  CAS  Google Scholar 

  5. Chen Y, Tong Y, Yang C, et al. Consumption of hot beverages and foods and the risk of esophageal cancer: a meta-analysis of observational studies. BMC Cancer. 2015;15:449.

    Article  Google Scholar 

  6. Matejcic M, Iqbal PM. Gene-environment interactions in esophageal cancer. Crit Rev Clin Lab Sci. 2015;52:211–231.

    Article  CAS  Google Scholar 

  7. Sawada G, Niida A, Uchi R, et al. Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology. 2016;150:1171–1182.

    Article  Google Scholar 

  8. Liu J, Wang J, Leng Y, Lv C. Intake of fruit and vegetables and risk of esophageal squamous cell carcinoma: a meta-analysis of observational studies. Int J Cancer. 2013;133:473–485.

    Article  CAS  Google Scholar 

  9. Yamashita K, Katada N, Moriya H, et al. Multimodality treatment and prognosis in esophageal squamous cell carcinoma requiring esophagectomy. Hepatogastroenterology. 2014;61:1042–1048.

    PubMed  Google Scholar 

  10. Kadota T, Hatogai K, Yano T, et al. Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients. Cancer Sci. 2018;109:2046–2055.

    Article  CAS  Google Scholar 

  11. Njei B, McCarty TR, Birk JW. Trends in esophageal cancer survival in United States adults from 1973 to 2009: a SEER database analysis. J Gastroenterol Hepatol. 2016;31:1141–1146.

    Article  Google Scholar 

  12. Li J, Gong Y, Diao P, et al. Comparison of the clinical efficacy between single-agent and dual-agent concurrent chemoradiotherapy in the treatment of unresectable esophageal squamous cell carcinoma: a multicenter retrospective analysis. Radiat Oncol. 2018;13:12.

    Article  Google Scholar 

  13. Rooney S, Ryan MF. Effects of α-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer Res. 2005;25:2199–2204.

    CAS  PubMed  Google Scholar 

  14. Lorent JH, Leonard C, Abouzi M, et al. α-Hederin induces apoptosis, membrane permeabilization and morphologic changes in two cancer cell lines through a cholesterol-dependent mechanism. Planta Med. 2016;82:1532–1539.

    Article  CAS  Google Scholar 

  15. Fallahi M, Keyhanmanesh R, Khamaneh AM, et al. Effect of α-hederin, the active constituent of Nigella sativa, on miRNA-126, IL-13 mRNA levels and inflammation of lungs in ovalbumin-sensitized male rats. Avic J Phytomed. 2016;6:77–85.

    CAS  Google Scholar 

  16. Keyhanmanesh R, Saadat S, Mohammadi M, Shahbazfar AA, Fallahi M. The protective effect of α-hederin, the active constituent of nigella sativa, on lung inflammation and blood cytokines in ovalbumin sensitized guinea pigs. Phytother Res. 2015;29:1761–1767.

    Article  CAS  Google Scholar 

  17. Gepdiremen A, Mshvildadze V, Suleyman H, Elias R. Acute anti-inflammatory activity of four saponins isolated from ivy: α-hederin, hederasaponin-C, hederacolchiside-E and hederacolchiside-F in carrageenan-induced rat paw edema. Phytomedicne. 2005;12:440–444.

    Article  CAS  Google Scholar 

  18. Li J, Wu DD, Zhang JX, et al. Mitochondrial pathway mediated by reactive oxygen species involvement in α-hederin-induced apoptosis in hepatocellular carcinoma cells. World J Gastroenterol. 2018;24:1901–1910.

    Article  CAS  Google Scholar 

  19. Cheng L, Xia TS, Wang YF, et al. The anticancer effect and mechanism of α-hederin on breast cancer cells. Int J Oncol. 2014;45:757–763.

    Article  CAS  Google Scholar 

  20. Sodrul I, Wang C, Chen X, Du J, Sun H. Role of ginsenosides in reactive oxygen species-mediated anticancer therapy. Oncotarget. 2018;9:2931–2950.

    Article  Google Scholar 

  21. Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50–64.

    Article  CAS  Google Scholar 

  22. Sosa V, Moline T, Somoza R, et al. Oxidative stress and cancer: an overview. Ageing Res Rev. 2013;12:376–390.

    Article  CAS  Google Scholar 

  23. Wu WS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 2006;25:695–705.

    Article  CAS  Google Scholar 

  24. Weinberg F, Chandel NS. Reactive oxygen species-dependent signaling regulates cancer. Cell Mol Life Sci. 2009;66:3663–3673.

    Article  CAS  Google Scholar 

  25. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14:709–721.

    Article  CAS  Google Scholar 

  26. Ding Y, Wang H, Niu J, et al. Induction of ROS overload by alantolactone prompts oxidative DNA damage and apoptosis in colorectal cancer cells. Int J Mol Sci. 2016;17:558.

    Article  Google Scholar 

  27. Aredia F, Czaplinski S, Fulda S, Scovassi AI. Molecular features of the cytotoxicity of an NHE inhibitor: evidence of mitochondrial alterations, ROS overproduction and DNA damage. BMC Cancer. 2016;16:851.

    Article  Google Scholar 

  28. Aquilano K, Baldelli S, Ciriolo MR. Glutathione: new roles in redox signaling for an old antioxidant. Front Pharmacol. 2014;5:196.

    Article  Google Scholar 

  29. Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med. 2013;62:90–101.

    Article  CAS  Google Scholar 

  30. Bertero E, Maack C. Calcium signaling and reactive oxygen species in mitochondria. Circ Res. 2018;122:1460–1478.

    Article  CAS  Google Scholar 

  31. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 1997;275:1132–1136.

    Article  CAS  Google Scholar 

  32. Reubold TF, Wohlgemuth S, Eschenburg S. A new model for the transition of APAF-1 from inactive monomer to caspase-activating apoptosome. J Biol Chem. 2009;284:32717–32724.

    Article  CAS  Google Scholar 

  33. Zhou M, Li Y, Hu Q, et al. Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1. Genes Dev. 2015;29:2349–2361.

    Article  CAS  Google Scholar 

  34. Edlich F. BCL-2 proteins and apoptosis: recent insights and unknowns. Biochem Biophys Res Commun. 2018;500:26–34.

    Article  CAS  Google Scholar 

  35. Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol. 1998;8:324–330.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study is supported by the National Natural Science Foundation of China (No. 81572426), the Natural Science Foundation of Hubei Province (No. 2015CKB755) and the Youth Fund of Beijing Shijitan Hospital (No. 2016-q07).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China

    Jing Wang, Hong Liu & Jing Wu

  2. Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, Hubei Province, People’s Republic of China

    Dandan Wu, Jixiang Zhang & Weiguo Dong

Authors
  1. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dandan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jixiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weiguo Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weiguo Dong.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Wu, D., Zhang, J. et al. α-Hederin Induces Apoptosis of Esophageal Squamous Cell Carcinoma via an Oxidative and Mitochondrial-Dependent Pathway. Dig Dis Sci 64, 3528–3538 (2019). https://doi.org/10.1007/s10620-019-05689-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-019-05689-1

Keywords

Search

Navigation