ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib
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Jiani Liu1,2,*, Jiangxue Wu1,*, Ling Zhou1,*, Changchuan Pan3, Yi Zhou1, Wuying Du1, Jie-min Chen1, Xiaofeng Zhu1, Jingnan Shen4, Shuai Chen1, Ran-yi Liu1 and Wenlin Huang1,5
1 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
2 Department of Oncology, Jingzhou Hospital, Tongji Medical College of Huazhong University of Science and Technology, Jingzhou, Hubei, China
3 Medical Oncology, Sichuan Cancer Hospital and Institute, Second People’s Hospital of Sichuan Province, Chengdu, China
4 Musculoskeletal Oncology Department, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
5 Guangdong Provincial Key Laboratory of Tumor Targeted Drugs and Guangzhou Enterprise Key Laboratory of Gene Medicine, Guangzhou Doublle Bioproducts Co. Ltd., Guangzhou, China
* These authors have contributed equally to this work
Wenlin Huang, email:
Ran-yi Liu, email:
Keywords: ZD6474; celecoxib; osteosarcoma; EGFR; cyclooxygenase-2
Received: December 14, 2014 Accepted: May 12, 2015 Published: May 19, 2015
ZD6474, a small molecule VEGFR and EGFR tyrosine kinase inhibitor, has been considered as a promising tumor-targeted drug in various malignancies. EGFR and cyclooxygenase-2 (COX-2) were found overexpressed in osteosarcoma in previous reports, so here we tried to explore the anti-osteosarcoma effect of ZD6474 alone or combination with celecoxib, a COX-2 inhibitor. The data demonstrated that ZD6474 inhibited the growth of osteosarcoma cells, and promoted G1-phase cell cycle arrest and apoptosis by inhibiting the activity of EGFR tyrosine kinase, and consequently suppressing its downstream PI3k/Akt and MAPK/ERK pathway. Additionally, daily administration of ZD6474 produced a dose-dependent inhibition of tumor growth in nude mice. Celecoxib also significantly inhibited the growth of osteosarcoma cells in dose-dependent manner, while combination of ZD6474 and celecoxib displayed a synergistic or additive antitumor effect on osteosarcoma in vitro and in vivo. The possible molecular mechanisms to address the synergism are likely that ZD6474 induces the down-regulation of COX-2 expression through inhibiting ERK phosphorylation, while celecoxib promotes ZD6474-directed inhibition of ERK phosphorylation. In conclusion, ZD6474 exerts direct anti-proliferative effects on osteosarcoma cells, and the synergistic antitumor effect of the combination of ZD6474 with celecoxib may indicate a new strategy of the combinative treatment of human osteosarcoma.
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