title: Inhibition of lung tumor growth by targeting EGFR/VEGFR-Akt/NF-κB pathways with novel theanine derivatives.
abstract: 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.
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, P R China.
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, P R China.
authors.forename: Xinshan
authors.initials: X
authors.lastname: Ye
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China; These authors contributed equally to this work.
authors.forename: Dexin
authors.initials: D
authors.lastname: Ji
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China; These authors contributed equally to this work.
authors.forename: Huarong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China; These authors contributed equally to this work.
authors.forename: Fujia
authors.initials: F
authors.lastname: Sun
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China; These authors contributed equally to this work.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Shang
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China; Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA; These authors contributed equally to this work.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
authors.forename: Fengfei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Tian
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yishan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hanchen
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Radiotherapy,307 Hospital of PLA,Academy of Military Medical Science,Beijing,P. R. China.
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
authors.affiliation: National Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan, Chaoyangqu, Beijing, P. R. China.
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Tea Biochemistry & Biotechnology, Ministry of Agriculture, Anhui Agricultural University, Hefei, Anhui Province, China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005971:Glutamates / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D005971:Glutamates; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C026166:theanine; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt