Tumor Biology

, Volume 37, Issue 5, pp 6987–6996 | Cite as

Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway

  • Ming-Te Lin
  • Chia-Liang Lin
  • Tzu-Yu Lin
  • Chun-Wen Cheng
  • Shun-Fa Yang
  • Chu-Liang Lin
  • Chih-Chien Wu
  • Yi-Hsien Hsieh
  • Jen-Pi Tsai
Original Article


Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.


Apoptosis Fisetin Cervical cancer Sorafenib Mitochondrial membrane potential 



This work was supported by grants from Chang Bing Show Chwan Memorial Hospital (RD104025).

Compliance with ethical standards

Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Ming-Te Lin
    • 1
    • 2
  • Chia-Liang Lin
    • 3
  • Tzu-Yu Lin
    • 4
  • Chun-Wen Cheng
    • 3
  • Shun-Fa Yang
    • 5
  • Chu-Liang Lin
    • 3
  • Chih-Chien Wu
    • 3
  • Yi-Hsien Hsieh
    • 3
    • 6
    • 7
  • Jen-Pi Tsai
    • 8
    • 9
  1. 1.Department of Obstetrics and GynecologyChang Bing Show Chwan Memorial HospitalChanghua CountyTaiwan
  2. 2.Liberal Arts CenterDa-Yeh UniversityChanghuaTaiwan
  3. 3.Institute of Biochemistry, Microbiology and ImmunologyChung Shan Medical UniversityTaichungTaiwan
  4. 4.Department of Biochemistry and Molecular Biology, College of Biological SciencesUniversity of California DavisDavisUSA
  5. 5.Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
  6. 6.Department of Biochemistry, School of MedicineChung Shan Medical UniversityTaichungTaiwan
  7. 7.Clinical LaboratoryChung Shan Medical University HospitalTaichungTaiwan
  8. 8.School of MedicineTzu Chi UniversityHualienTaiwan
  9. 9.Department of Internal Medicine, Division of NephrologyDalin Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationChiayiTaiwan

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