Inhibition of lung tumor growth by targeting EGFR/VEGFR-Akt/NF-κB pathways with novel theanine derivatives
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Guoying Zhang1,2, Xinshan Ye2, Dexin Ji1,*, Huarong Zhang1,*, Fujia Sun1,*, Chunqing Shang1,*, Ying Zhang1,3,*, Erxi Wu3, Fengfei Wang3, Fei Wu1, Huihui Tian1, Xin Liu1, Linlin Chen1, Kun Liu1,Yishan Wang4, Hanchen Liu4, Wenhua Zhang4, Yukun Guan1, Qinwen Wang5, Xiaohang Zhao6 and Xiaochun Wan7
1 Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China
2 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, P R China
3 Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA
4 The Center of Non-Traumatic Treatment and Diagnosis of Tumor, Binzhou Medical College affiliated The PLA 107 Hospital, Southern Zhichu Road, Yantai, Shandong Province, China
5 Department of Radiotherapy,307 Hospital of PLA,Academy of Military Medical Science,Beijing,P. R. China
6 National Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan, Chaoyangqu, Beijing, P. R. China
7 Key Laboratory of Tea Biochemistry & Biotechnology, Ministry of Agriculture, Anhui Agricultural University, Hefei, Anhui Province, China
* These authors contributed equally to this work
Guoying Zhang, email:
Xiaochun Wan, email:
Xinshan Ye, email:
Yukun Guan, email:
Wenqin Wang, email:
Xiaohang Zhao, email:
Keywords: Theanine derivatives, lung cancer, growth and migration, xenograft mouse models, inhibition, EGFR/VEGFR-Akt-NF-κB pathways
Received: May 14, 2014 Accepted: August 09, 2014 Published: August 10, 2014
The molecularly targeted agents, including anti-VEGF or anti-EGFR monoclonal antibody and some inhibitors of EGFR tyrosine kinase, are effective in the treatment of non-small-cell lung cancer (NSCLC) to a certain extent, but the benefit for a proportion of patients is still limited. Hence, it is necessary and urgent to develop more selective and effective molecular targeted agents against lung cancer. Here, we have synthesized novel theanine derivatives, methyl coumarin-3-carboxylyl L-theanine (TMC), ethyl coumarin-3-carboxylyl L-theanine (TEC), ethyl 6-fluorocoumarin- 3-carboxylyl L-theanine (TFC), and ethyl 6-nitrocoumarin-3-carboxylyl L-theanine (TNC), which are fluorescent small molecules, based on their parental compound theanine and studied their anticancer activities in vitro, ex vivo and in vivo models of human and mouse cancers. Our results show that the four theanine derivatives significantly inhibit the lung cancer cell migration and the growth of lung cancer and leukemia cell lines. TFC and TNC display enhanced effects with anticancer drugs cytarabine, vincristine, and methotrexate on inhibition of lung cancer cell growth and no toxicity to the normal human embryonic lung fibroblast and peripheral blood lymphocytes. TFC and TNC exhibit strong suppression of the highly metastatic Lewis lung cancer (LLC) and A549 tumor growth in tumor-bearing mice without toxicity to mice. TFC and TNC can effectively suppress the growth of lung cancer cells in vitro, ex vivo and in vivo by targeting EGFR/VEGFR-Akt/NF-κB pathways. Our study has suggested that TFC and TNC may have the therapeutic and/or adjuvant therapeutic applications in the treatment of lung cancers and other cancer.
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