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Epidermal growth factor receptor(EGFR),a transmembrane glycoprotein,is expressed at high levels in a large proportion of laryngeal squamous cell carcinoma(LSCC).Cetuximab(Cet),an anti-EGFR monoclonal antibody,has limited clinical outcome for patients with head and neck squamous cell carcinoma.Our previous studies showed that oridonin(ORI),a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens,inhibited cell growth in HEp-2 cells through inhibition of EGFR phosphorylation.The purpose of this study was to determine whether ORI could improve the anti-cancer efficacy of Cet on LSCC.We observed that the combination with Cet and ORI synergistically inhibited cell growth associated with Fas-mediated apoptosis and G2/M phase arrest in two LSCC cell lines(HEp-2 and Tu212 cells).Moreover,combination treatment caused cell death associated with suppression of EGFR and activation of reactive oxygen species(ROS)-mediated JNK pathway.In nude mice bearing HEp-2 xenografts,ORI plus Cet caused a significant tumor regression through induction apoptosis and inhibition proliferation with no side effect.Together,our findings suggest that the combination of ORI and Cet has the potential to enhance tumor responses,and may significantly improve therapeutic outcomes in LSCC.