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Oncotarget. 2015 Aug 28;6(25):21341-52.

ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib.

Author information

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.

Abstract

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.

KEYWORDS:

EGFR; ZD6474; celecoxib; cyclooxygenase-2; osteosarcoma

PMID:
26050198
PMCID:
PMC4673269
DOI:
10.18632/oncotarget.4179
[Indexed for MEDLINE]
Free PMC Article

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