Skip to main content

Advertisement

Log in

Britannin, a sesquiterpene lactone, inhibits proliferation and induces apoptosis through the mitochondrial signaling pathway in human breast cancer cells

  • Research Article
  • Published:
Tumor Biology

Abstract

Induction of apoptosis in cancer cells can be a promising treatment method in cancer therapy. Naturally derived products had drawn growing attention as agent in cancer therapy. The main target of anticancer drugs may be distinct, but eventually, they lead to identical cell death pathway, which is apoptosis. Here, we indicated that britannin, a sesquiterpene lactone isolated from Asteraceae family, has antiproliferative activity on the MCF-7 and MDA-MB-468 human breast cancer cells. Annexin V/propidium iodide (PI) staining, Hoechst 33258 staining, and caspase-3/9 activity assay confirmed that britannin is able to induce apoptosis in MCF-7 and MDA-MB-468 cells. The Western blot analysis showed that the expression of Bcl-2 was noticeably decreased in response to britannin treatment, while the expression of Bax protein was increased, which were positively correlated with elevated expression of p53. Moreover, britannin also increased reactive oxygen species (ROS) generation which in turn triggered the loss of mitochondrial transmembrane potential (ΔΨm) and the subsequent release of cytochrome c from mitochondria into cytosol. Taken together, these results suggest that britannin inhibits growth of MCF-7 and MDA-MB-468 breast cancer cells through the activation of the mitochondrial apoptotic pathway and may potentially serve as an agent for breast cancer therapy.

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

Access this article

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. M Y, Ahmadi M R H, J K, H P, K H A, M R Y, K H. An 8 years retrospective study of breast cancer incidence in Ilam province, Western Iran. J Clin Diagn Res. 2013;7:2923–25.

  2. Head J, Johnston SR. New targets for therapy in breast cancer: farnesyltransferase inhibitors. Breast Cancer Res. 2004;6:262–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mann J. Natural products in cancer chemotherapy: past, present and future. Nat Rev Cancer. 2002;2:143–8.

    Article  CAS  PubMed  Google Scholar 

  4. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005;4:206–20.

    Article  CAS  PubMed  Google Scholar 

  5. Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75:311–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Butler MS. The role of natural product chemistry in drug discovery. J Nat Prod. 2004;67:2141–53.

    Article  CAS  PubMed  Google Scholar 

  7. Paterson I, Anderson EA. Chemistry. The renaissance of natural products as drug candidates. Science. 2005;310:451–3.

    Article  PubMed  Google Scholar 

  8. Cragg GM, Newman DJ. Antineoplastic agents from natural sources: achievements and future directions. Expert Opin Investig Drugs. 2000;9:2783–97.

    Article  CAS  PubMed  Google Scholar 

  9. Kaczirek K, Schindl M, Weinhäusel A, Scheuba C, Passler C, Prager G, et al. Cytotoxic activity of camptothecin and paclitaxel in newly established continuous human medullary thyroid carcinoma cell lines. J Clin Endocrinol Metab. 2004;89:2397–401.

    Article  CAS  PubMed  Google Scholar 

  10. Al Dhaheri Y, Eid A, AbuQamar S, Attoub S, Khasawneh M, Aiche G, et al. Mitotic arrest and apoptosis in breast cancer cells induced by Origanum majorana extract: upregulation of TNF-α and downregulation of survivin and mutant p53. PLoS One. 2013;8:e56649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhao YM, Zhang ML, Shi QW, Kiyota H. Chemical constituents of plants from the genus Inula. Chem Biodivers. 2006;3:371–84.

    Article  CAS  PubMed  Google Scholar 

  12. Chadwick M, Trewin H, Gawthrop F, Wagstaff C. Sesquiterpenoids lactones: benefits to plants and people. Int J Mol Sci. 2013;14:12780–805.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA, Darwiche N. What made sesquiterpene lactones reach cancer clinical trials? Drug Discov Today. 2010;15:668–78.

    Article  CAS  PubMed  Google Scholar 

  14. Merfort I. Perspectives on sesquiterpene lactones in inflammation and cancer. Curr Drug Targets. 2011;12:1560–73.

    Article  CAS  PubMed  Google Scholar 

  15. Kreuger MR, Grootjans S, Biavatti MW, Vandenabeele P, D’Herde K. Sesquiterpene lactones as drugs with multiple targets in cancer treatment: focus on parthenolide. Anticancer Drugs. 2012;23:883–96.

    PubMed  Google Scholar 

  16. Moghadam MH, Hajimehdipoor H, Saeidnia S, Atoofi A, Shahrestani R, Read RW, et al. Anti-proliferative activity and apoptotic potential of britannin, a sesquiterpene lactone from Inula aucheriana. Nat Prod Commun. 2012;7:979–80.

    CAS  PubMed  Google Scholar 

  17. Fallahian F, Karami-Tehrani F, Salami S. Induction of apoptosis by type Iβ protein kinase G in the human breast cancer cell lines MCF-7 and MDA-MB-468. Cell Biochem Funct. 2012;30:183–90.

    Article  CAS  PubMed  Google Scholar 

  18. Shirali S, Aghaei M, Shabani M, Fathi M, Sohrabi M, Moeinifard M. Adenosine induces cell cycle arrest and apoptosis via cyclinD1/Cdk4 and Bcl-2/Bax pathways in human ovarian cancer cell line OVCAR-3. Tumour Biol. 2013;34:1085–95.

    Article  CAS  PubMed  Google Scholar 

  19. Polager S, Ginsberg D. p53 and E2f: partners in life and death. Nat Rev Cancer. 2009;9:738–48.

    Article  CAS  PubMed  Google Scholar 

  20. Cosentino K, García-Sáez AJ. Mitochondrial alterations in apoptosis. Chem Phys Lipids. 2014;181:62–75. doi:10.1016/j.chemphyslip.2014.04.001.

  21. Weitsman GE, Ravid A, Liberman UA, Koren R. Vitamin D enhances caspase-dependent and independent TNF-induced breast cancer cell death: the role of reactive oxygen species. Ann N Y Acad Sci. 2003;1010:437–40.

    Article  CAS  PubMed  Google Scholar 

  22. Fulda S. Modulation of apoptosis by natural products for cancer therapy. Planta Med. 2010;76:1075–9.

    Article  CAS  PubMed  Google Scholar 

  23. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992;148:2207–16.

    CAS  PubMed  Google Scholar 

  24. Schutte B, Nuydens R, Geerts H, Ramaekers F. Annexin V binding assay as a tool to measure apoptosis in differentiated neuronal cells. J Neurosci Methods. 1998;86:63–9.

    Article  CAS  PubMed  Google Scholar 

  25. Benchimol S. p53-dependent pathways of apoptosis. Cell Death Differ. 2001;8:1049–51.

    Article  CAS  PubMed  Google Scholar 

  26. Oren M. Decision making by p53: life, death and cancer. Cell Death Differ. 2003;10:431–42.

    Article  CAS  PubMed  Google Scholar 

  27. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305:626–9.

    Article  CAS  PubMed  Google Scholar 

  28. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human Bax gene. Cell. 1995;80:293–9.

    Article  CAS  PubMed  Google Scholar 

  29. Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7:880–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vogler M, Hamali HA, Sun XM. BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood. 2011;117:7145–54.

    Article  CAS  PubMed  Google Scholar 

  31. Jänicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem. 1998;273:9357–60.

    Article  PubMed  Google Scholar 

  32. Fallahian F, Karami-Tehrani F, Salami S, Aghaei M. Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor-positive and -negative breast cancer cell lines. FEBS J. 2011;278:3360–9.

    Article  CAS  PubMed  Google Scholar 

  33. Engel RH, Evens AM. Oxidative stress and apoptosis: a new treatment paradigm in cancer. Front Biosci. 2006;11:300–12.

    Article  CAS  PubMed  Google Scholar 

  34. Fiers W, Beyaert R, Declercq W, Vandenabeele P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene. 1999;18:7719–30.

    Article  CAS  PubMed  Google Scholar 

  35. Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000;5:415–8.

    Article  CAS  PubMed  Google Scholar 

  36. Le Bras M, Clément MV, Pervaiz S, Brenner C. Reactive oxygen species and the mitochondrial signaling pathway of cell death. Histol Histopathol. 2005;20:205–19.

    PubMed  Google Scholar 

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Faranak Fallahian.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hamzeloo-Moghadam, M., Aghaei, M., Fallahian, F. et al. Britannin, a sesquiterpene lactone, inhibits proliferation and induces apoptosis through the mitochondrial signaling pathway in human breast cancer cells. Tumor Biol. 36, 1191–1198 (2015). https://doi.org/10.1007/s13277-014-2744-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2744-9

Keywords

Navigation