9-Oxo-(10E,12E)-octadecadienoic acid, a cytotoxic fatty acid ketodiene isolated from eggplant calyx, induces apoptosis in human ovarian cancer (HRA) cells

Abstract

9-Oxo-(10E,12E)-octadecadienoic acid (9-EE-KODE), which is isolated from the calyx of eggplants, exhibits cytotoxic activity against human ovarian cancer (HRA) cells. The aim of the present study is to clarify the action mechanism of 9-EE-KODE leading to cell death. After the treatment of 9-EE-KODE in HRA cells, we found intracellular DNA fragmentation, surface-exposure of phosphatidylserine in the outer cell membrane, and increased caspase-3/7 activities in the HRA cells. The dissipation of mitochondrial membrane potential, release of cytochrome c from mitochondria to cytosol, down-regulation of Bcl-2, and up-regulation of Bax levels were also found in 9-EE-KODE-treated cells in a dose-dependent manner. These results demonstrated that 9-EE-KODE induced apoptosis in HRA cells via the mitochondrial regulation pathway.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. 1.

    Inami K, Aida T (2006) Yakusou (medicinal plants). Yama-to-Keikokusha, Tokyo, pp 138–139

    Google Scholar 

  2. 2.

    Tomoda Y, Tomoda K, Horio H, Mano N, Mano S, Morikawa Y, Ito T, Sugiyama M (2007) Treatment outcome of Condyloma acuminatum. In: Proceedings of the 18th Annual Meeting of the Japanese Society of Sexually Transmitted Infections, Kokura, Japan, abstract B-31

  3. 3.

    Zhao B, Sakurai Y, Shibata K, Kikkawa F, Tomoda T, Mizukami H (2014) Cytotoxic fatty acid ketodiens from eggplants. Jap J Food Chem Safety 21:42–47

    CAS  Google Scholar 

  4. 4.

    Kierszenbaum AL, Tres L (2011) Histology and cell biology: an introduction to pathology. Elsevier, Philadelphia

    Google Scholar 

  5. 5.

    Harding KE, May LM, Dick KF (1975) Selective oxidation of allylic alcohols with chromic acid. J Org Chem 40:1664–1665

    CAS  Article  Google Scholar 

  6. 6.

    Tsuboi S, Maeda S, Takeda A (1986) A convenient synthesis of (±)-dimorphecolic acid and its analogs. Bull Chem Soc Jpn 59:2050–2052

    CAS  Article  Google Scholar 

  7. 7.

    Kikuchi Y, Kizawa I, Oomori K, Miyauchi M, Kita T, Sugita M, Tenjin Y, Kato K (1987) Establishment of a human ovarian cancer cell line capable of forming ascites in nude mice and effects of tranexamic acid on cell proliferation and ascites formation. Cancer Res 47:592–596

    CAS  PubMed  Google Scholar 

  8. 8.

    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Khodarev NN, Sokolova IA, Vaughan AT (1998) Mechanisms of induction of apoptotic DNA fragmentation. Int J Radiat Biol 73:455–467

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Bevers EM, Comfurius P, Zwaal RF (1996) Regulatory mechanisms in maintenance and modulation of transmembrane lipid asymmetry: pathophysiological implications. Lupus 5:480–487

    CAS  PubMed  Google Scholar 

  11. 11.

    Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31:1–9

    PubMed  Article  Google Scholar 

  13. 13.

    Ou L, Ip C, Lisafeld B, Ip MM (2007) Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss. Biochem Biophys Res Commun 356:1044–1049

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  14. 14.

    Tsujimoto Y (1998) Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells 3:697–707

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Pierre AS, Minville-Walz M, Fèvre C, Hichami A, Gresti J, Pichon L, Bellenger S, Bellenger J, Ghiringhelli F, Narce M, Rialland M (2013) Trans-10, cis-12 conjugated linoleic acid induced cell death in human colon cancer cells through reactive oxygen species-mediated ER stress. Biochim Biophys Acta 1831:759–768

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kim YI, Hirai S, Goto T, Ohyane C, Takahashi H, Tsugane T, Konishi C, Fujii T, Inai S, Iijima Y, Aoki K, Shibata D, Takahashi N, Kawada T (2012) Potent PPARα activator derived from tomato juice, 13-oxo-9,11-octadecadienoic acid, decreases plasma and hepatic triglyceride in obese diabetic mice. PLoS One 7:e31317

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Prof. Tsunehiko Higuchi and Dr. Nobuki Kato, Graduate School of Pharmaceutical Sciences, Nagoya City University for supporting the synthesis of 9-EE-KODE. We also thank Dr. Kiyosumi Shibata, Graduate School of Medicine, Nagoya University for providing us with the HRA cell line.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Toshiaki Makino.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhao, B., Tomoda, Y., Mizukami, H. et al. 9-Oxo-(10E,12E)-octadecadienoic acid, a cytotoxic fatty acid ketodiene isolated from eggplant calyx, induces apoptosis in human ovarian cancer (HRA) cells. J Nat Med 69, 296–302 (2015). https://doi.org/10.1007/s11418-015-0892-x

Download citation

Keywords

  • 9-Oxo-(10E,12E)-octadecadienoic acid
  • Ovarian cancer cell
  • Apoptosis
  • Mitochondrial pathway