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.
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.
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.
Shijie
S
Cao
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.
Meijuan
M
Xia
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.
Yiwei
Y
Mao
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China.
Qiang
Q
Zhang
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.
Paul Owusu
PO
Donkor
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.
Feng
F
Qiu
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China.
Ning
N
Kang
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000008:administration & dosage; D045786:Diterpenes, Kaurane / Q000008:administration & dosage; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007822:Laryngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D045786:Diterpenes, Kaurane; D017382:Reactive Oxygen Species; C011959:oridonin; C512478:EGFR protein, human; D066246:ErbB Receptors; D048670:MAP Kinase Kinase 4; D000068818:Cetuximab