Advertisement

Tumor Biology

, Volume 36, Issue 2, pp 1191–1198 | Cite as

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

  • Maryam Hamzeloo-Moghadam
  • Mahmoud Aghaei
  • Faranak Fallahian
  • Seyyed Mehdi Jafari
  • Masoumeh Dolati
  • Mohammad Hossein Abdolmohammadi
  • Sima Hajiahmadi
  • Somayeh Esmaeili
Research Article

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.

Keywords

Sesquiterpene lactone Britannin Apoptosis Breast cancer MCF-7 MDA-MB-468 

Notes

Conflicts of interest

None.

References

  1. 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.Google Scholar
  2. 2.
    Head J, Johnston SR. New targets for therapy in breast cancer: farnesyltransferase inhibitors. Breast Cancer Res. 2004;6:262–8.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mann J. Natural products in cancer chemotherapy: past, present and future. Nat Rev Cancer. 2002;2:143–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005;4:206–20.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Butler MS. The role of natural product chemistry in drug discovery. J Nat Prod. 2004;67:2141–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Paterson I, Anderson EA. Chemistry. The renaissance of natural products as drug candidates. Science. 2005;310:451–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Cragg GM, Newman DJ. Antineoplastic agents from natural sources: achievements and future directions. Expert Opin Investig Drugs. 2000;9:2783–97.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhao YM, Zhang ML, Shi QW, Kiyota H. Chemical constituents of plants from the genus Inula. Chem Biodivers. 2006;3:371–84.CrossRefPubMedGoogle Scholar
  12. 12.
    Chadwick M, Trewin H, Gawthrop F, Wagstaff C. Sesquiterpenoids lactones: benefits to plants and people. Int J Mol Sci. 2013;14:12780–805.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 14.
    Merfort I. Perspectives on sesquiterpene lactones in inflammation and cancer. Curr Drug Targets. 2011;12:1560–73.CrossRefPubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 19.
    Polager S, Ginsberg D. p53 and E2f: partners in life and death. Nat Rev Cancer. 2009;9:738–48.CrossRefPubMedGoogle Scholar
  20. 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. 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.CrossRefPubMedGoogle Scholar
  22. 22.
    Fulda S. Modulation of apoptosis by natural products for cancer therapy. Planta Med. 2010;76:1075–9.CrossRefPubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 25.
    Benchimol S. p53-dependent pathways of apoptosis. Cell Death Differ. 2001;8:1049–51.CrossRefPubMedGoogle Scholar
  26. 26.
    Oren M. Decision making by p53: life, death and cancer. Cell Death Differ. 2003;10:431–42.CrossRefPubMedGoogle Scholar
  27. 27.
    Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305:626–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human Bax gene. Cell. 1995;80:293–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7:880–5.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 33.
    Engel RH, Evens AM. Oxidative stress and apoptosis: a new treatment paradigm in cancer. Front Biosci. 2006;11:300–12.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 35.
    Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000;5:415–8.CrossRefPubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Maryam Hamzeloo-Moghadam
    • 1
    • 5
  • Mahmoud Aghaei
    • 2
  • Faranak Fallahian
    • 3
  • Seyyed Mehdi Jafari
    • 4
    • 6
  • Masoumeh Dolati
    • 3
  • Mohammad Hossein Abdolmohammadi
    • 3
  • Sima Hajiahmadi
    • 2
  • Somayeh Esmaeili
    • 5
  1. 1.Traditional Medicine and Materia Medica Research CenterShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Department of Clinical Biochemistry School of Pharmacy and Pharmaceutical SciencesIsfahan University of Medical SciencesIsfahanIran
  3. 3.Cellular and Molecular Research CenterQom University of Medical SciencesQomIran
  4. 4.Department of Clinical Biochemistry, School of MedicineZahedan University of Medical SciencesZahedanIran
  5. 5.Department of Traditional Pharmacy, School of Traditional MedicineShahid Beheshti University of Medical SciencesTehranIran
  6. 6.Cellular and Molecular Research CenterZahedan University of Medical SciencesZahedanIran

Personalised recommendations