Archives of Toxicology

, Volume 86, Issue 2, pp 263–273 | Cite as

Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway

  • Tsung-Ho Ying
  • Shun-Fa Yang
  • Su-Ju Tsai
  • Shu-Ching Hsieh
  • Yi-Chang Huang
  • Da-Tian BauEmail author
  • Yi-Hsien HsiehEmail author
In vitro systems


Fisetin is a naturally occurring flavonoid that has been reported to inhibit the proliferation and to induce apoptotic cell death in several tumor cells. However, the apoptosis-inducing effect of fisetin on tumor cell lines was investigated besides HeLa cells. In this study, we found that fisetin induced apoptosis of HeLa cells in a dose- and time-dependent manner, as evidenced by nuclear staining of 4′-6-Diamidino-2-phenylindole (DAPI), flow cytometry assay, and Annexin-V/PI double-labeling. In addition, fisetin triggered the activations of caspases-3 and -8 and the cleavages of poly (ADP-ribose) polymerase, resulting in apoptosis induction. Moreover, treatment of HeLa cells with fisetin induced a sustained activation of the phosphorylation of ERK1/2, and inhibition of ERK1/2 by PD98059 (MEK1/2 inhibitor) or transfection with the mutant ERK1/2 expression vector significantly abolished the fisetin-induced apoptosis through the activation of caspase-8/-3 pathway. The in vivo xenograft mice experiments revealed that fisetin significantly reduced tumor growth in mice with HeLa tumor xenografts. In conclusion, our results indicated that fisetin exhibited anti-cancer effect and induced apoptosis in HeLa cell lines both in vitro and in vivo.


Fisetin Apoptosis Cervical cancer Caspase ERK1/2 HeLa cell 



This work was supported by grants from National Science Council, Taiwan (NSC 98-2314-B-040-024) and Chung Shan Medical Hospital, Taichung, Taiwan (CSH-2011-C-026). Freeze centrifuge was performed in the Instrument Center of Chung Shan Medical University, which is supported by National Science Council, Ministry of Education and Chung Shan Medical University.

Conflict of interest

The authors declare that there is no conflict of interest.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Tsung-Ho Ying
    • 1
  • Shun-Fa Yang
    • 2
    • 3
  • Su-Ju Tsai
    • 4
    • 5
  • Shu-Ching Hsieh
    • 2
  • Yi-Chang Huang
    • 6
  • Da-Tian Bau
    • 7
    Email author
  • Yi-Hsien Hsieh
    • 6
    • 8
    Email author
  1. 1.Department of Obstetrics and Gynecology, School of Medicine, College of MedicineChung Shan Medical UniversityTaichungTaiwan
  2. 2.Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
  3. 3.Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
  4. 4.Department of Physical Medicine and RehabilitationChung Shan Medical University HospitalTaichungTaiwan
  5. 5.Department of Physical Medicine and Rehabilitation, College of MedicineChung Shan Medical UniversityTaichungTaiwan
  6. 6.Institute of Biochemistry and Biotechnology, College of MedicineChung Shan Medical UniversityTaichungTaiwan
  7. 7.Graduate Institute of Clinical Medical ScienceChina Medical UniversityTaichungTaiwan
  8. 8.Department of Biochemistry, School of Medicine, Chung Shan Medical University Clinical LaboratoryChung Shan Medical University HospitalTaichungTaiwan

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