Inhibition of lung tumor growth by targeting EGFR/VEGFR-Akt/NF-κB pathways with novel theanine derivatives

• DOI: 10.18632/oncotarget.2336
• Publication Date: 2015-09-15T23:38:12Z
• Authors: Guoying Zhang; Xinshan Ye; Dexin Ji; Huarong Zhang; Fujia Sun; Chunqing Shang; Ying Zhang; Erxi Wu; Fengfei Wang; Fei Wu; Huihui Tian; Xin Liu; Linlin Chen; Kun Liu; Yishan Wang; Hanchen Liu; Wenhua Zhang; Yukun Guan; Qinwen Wang; Xiaohang Zhao; Xiaochun Wan
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Leukemia; Lung Neoplasms; Dose-Response Relationship, Drug; Mice, Nude; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; 3. Good health; ErbB Receptors; Mice, Inbred C57BL; Carcinoma, Lewis Lung; 03 medical and health sciences; Glutamates; Cell Movement; Drug Design; Animals; Humans; Female; Apoptosis Regulatory Proteins; K562 Cells; Cell Proliferation

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, andmethotrexate 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.