Zhang Guoying, Ye Xinshan, Ji Dexin, Zhang Huarong, Sun Fujia, Shang Chunqing, Zhang Ying, Wu Erxi, Wang Fengfei, Wu Fei, Tian Huihui, Liu Xin, Chen Linlin, Liu Kun, Wang Yishan, Liu Hanchen, Zhang Wenhua, Guan Yukun, Wang Qinwen, Zhao Xiaohang, Wan Xiaochun
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.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, P R China.
Oncotarget. 2014 Sep 30;5(18):8528-43. doi: 10.18632/oncotarget.2336.
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.
分子靶向药物，包括抗血管内皮生长因子（VEGF）或抗表皮生长因子受体（EGFR）单克隆抗体以及一些EGFR酪氨酸激酶抑制剂，在一定程度上对非小细胞肺癌（NSCLC）的治疗有效，但对部分患者的益处仍然有限。因此，开发更具选择性和有效性的抗肺癌分子靶向药物既必要又紧迫。在此，我们基于母体化合物茶氨酸合成了新型茶氨酸衍生物，香豆素-3-羧基-L-茶氨酸甲酯（TMC）、香豆素-3-羧基-L-茶氨酸乙酯（TEC）、6-氟香豆素-3-羧基-L-茶氨酸乙酯（TFC）和6-硝基香豆素-3-羧基-L-茶氨酸乙酯（TNC），它们是荧光小分子，并在人源和小鼠癌症的体外、离体及体内模型中研究了它们的抗癌活性。我们的结果表明，这四种茶氨酸衍生物显著抑制肺癌细胞迁移以及肺癌和白血病细胞系的生长。TFC和TNC与抗癌药物阿糖胞苷、长春新碱和甲氨蝶呤联合使用时，对肺癌细胞生长的抑制作用增强，且对正常人胚肺成纤维细胞和外周血淋巴细胞无毒性。TFC和TNC对荷瘤小鼠体内高转移性Lewis肺癌（LLC）和A549肿瘤的生长具有强烈抑制作用，且对小鼠无毒性。TFC和TNC可通过靶向EGFR/VEGFR-Akt/NF-κB信号通路在体外、离体及体内有效抑制肺癌细胞生长。我们的研究表明，TFC和TNC可能在肺癌及其他癌症的治疗和/或辅助治疗中具有应用价值。
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