Guan Siao-Syun, Chang Jungshan, Cheng Chun-Chia, Luo Tsai-Yueh, Ho Ai-Sheng, Wang Chia-Chi, Wu Cheng-Tien, Liu Shing-Hwa
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan.
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Oncotarget. 2014 Jul 15;5(13):4868-80. doi: 10.18632/oncotarget.2050.
Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo.
结直肠癌（CRC）是全球常见的恶性肿瘤。表皮生长因子受体（EGFR）/人表皮生长因子受体2（HER2）在结直肠癌中的作用尚不清楚。阿法替尼是一种不可逆的EGFR/HER2抑制剂。关于阿法替尼治疗结直肠癌的研究较少。在此，我们研究了结直肠癌患者血清和肿瘤中HER2的蛋白水平/表达情况，以及阿法替尼在体外和体内对HER2过表达的结直肠癌的治疗效果。在收集的结直肠癌患者血清和肿瘤中检测到HER2水平升高。患者血清HER2水平与肿瘤HER2表达相关。阿法替尼还抑制HER2阳性肿瘤细胞的生长，并导致HER2过表达的人结直肠癌HCT-15细胞凋亡，但对HER2低表达的人胃癌MKN45细胞无此作用。体内研究表明，阿法替尼可降低HER2过表达异种移植瘤的生长。此外，与单独使用阿法替尼相比，阿法替尼胶束在HCT-15细胞中显示出更高的细胞毒性活性，并且在抑制HCT-15诱导的肿瘤异种移植瘤生长方面更有效。综上所述，这些发现表明，较高的血清HER2水平反映了结直肠癌患者肿瘤中较高的HER2含量，并且改良的阿法替尼胶束在体外和体内对HER2过表达的结直肠癌具有很高的治疗效果。
