Combined oridonin with cetuximab treatment shows synergistic anticancer effects on laryngeal squamous cell carcinoma: involvement of inhibition of EGFR and activation of reactive oxygen species-mediated JNK pathway

Cao,Shijie; Xia,Meijuan; Mao,Yiwei; Zhang,Qiang; Donkor,Paul Owusu; Qiu,Feng; Kang,Ning

doi:10.3892/ijo.2016.3696

Combined oridonin with cetuximab treatment shows synergistic anticancer effects on laryngeal squamous cell carcinoma: involvement of inhibition of EGFR and activation of reactive oxygen species-mediated JNK pathway

Authors:
- Shijie Cao
- Meijuan Xia
- Yiwei Mao
- Qiang Zhang
- Paul Owusu Donkor
- Feng Qiu
- Ning Kang
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Affiliations: Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China, School of Chinese Materia Medica, Tianjin State Key Laboratory of Modern Chinese Medicine and Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
Published online on: September 19, 2016 https://doi.org/10.3892/ijo.2016.3696
Pages: 2075-2087

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Abstract

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 aim of the present study was to determine whether ORI could improve the anticancer 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 p-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 of apoptosis and inhibition of 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.

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