Journal
ONCOTARGET
Volume 5, Issue 18, Pages 8528-8543Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2336
Keywords
Theanine derivatives; lung cancer; growth and migration; xenograft mouse models; inhibition; EGFR/VEGFR-Akt-NF-kappa B pathways
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Funding
- grant (863) from the Ministry of Science and Technology of the People's Republic of China [2012AA020206]
- Ministry of Human Resources and Social Security of the People's Republic of China
- Yantai University
- National Natural Science Foundation of China [30973553]
- Department of Science and Technology of Shandong Province [ZR2012HM016, 2009GG10002087]
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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-kappa B 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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