, Volume 24, Issue 1–2, pp 33–45 | Cite as

Molecular mechanisms of apoptosis and autophagy elicited by combined treatment with oridonin and cetuximab in laryngeal squamous cell carcinoma

  • Shijie Cao
  • Yiyuan Huang
  • Qiang Zhang
  • Fangjin Lu
  • Paul Owusu Donkor
  • Yan Zhu
  • Feng Qiu
  • Ning KangEmail author


Combined oridonin (ORI), a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens, and cetuximab (Cet), an anti-EGFR monoclonal antibody, have been reported to exert synergistic anti-tumor effects against laryngeal squamous cell carcinoma (LSCC) both in vitro and in vivo by our group. In the present study, we further found that ORI/Cet treatment not only resulted in apoptosis but also induced autophagy. AMPK/mTOR signaling pathway was found to be involved in the activation of autophagy in ORI/Cet-treated LSCC cells, which is independent of p53 status. Additionally, chromatin immunoprecipitation (ChIP) assay showed that ORI/Cet significantly increased the binding NF-κB family member p65 with the promotor of BECN 1, and p65-mediated up-regulation of BECN 1 caused by ORI/Cet is coupled to increased autophagy. On the other hand, we demonstrated that either Beclin 1 SiRNA or autophagy inhibitors could increase ORI/Cet induced-apoptosis, indicating that autophagy induced by combination of the two agents plays a cytoprotective role. Interestingly, 48 h after the combined treatment, autophagy began to decrease but apoptosis was significantly elevated. Our findings suggest that autophagy might be strongly associated with the antitumor efficacy of ORI/Cet, which may be beneficial to the clinical application of ORI/Cet in LSCC treatment.


Cetuximab Oridonin Autophagy Apoptosis Laryngeal squamous cell carcinoma 



This work was supported by the National Natural Science Foundation of China (Grant Numbers: 81373797 and 81102855). This study is also supported by the China Postdoctoral Science Special Foundation (Grant Number: 2014T70224) and the China Postdoctoral Science Foundation (Grant Number: 2013M541192).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10495_2018_1497_MOESM1_ESM.tif (258 kb)
Supplementary material 1 (TIF 258 KB)
10495_2018_1497_MOESM2_ESM.docx (13 kb)
Supplementary material 1 (DOCX 13 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Shijie Cao
    • 2
  • Yiyuan Huang
    • 1
    • 2
  • Qiang Zhang
    • 1
  • Fangjin Lu
    • 3
  • Paul Owusu Donkor
    • 4
  • Yan Zhu
    • 2
  • Feng Qiu
    • 3
  • Ning Kang
    • 1
    Email author
  1. 1.School of Integrative MedicineTianjin University of Traditional Chinese MedicineTianjinPeople’s Republic of China
  2. 2.Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinPeople’s Republic of China
  3. 3.School of Chinese Materia MedicaTianjin University of Traditional Chinese MedicineTianjinPeople’s Republic of China
  4. 4.School of PharmacyUniversity of Health and Allied SciencesHoGhana

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