https://scholars.lib.ntu.edu.tw/handle/123456789/639941
標題: | A novel EGFR inhibitor suppresses survivin expression and tumor growth in human gefitinib-resistant EGFR-wild type and -T790M non-small cell lung cancer | 作者: | Wang, Su-Pei Hsu, Ya-Ping CHIEN-JEN CHANG Chan, Yu-Chi Chen, Chien-Hung Wang, Rou-Hsin Liu, Kuang-Kai Pan, Pei-Ying Wu, Ya-Hui Yang, Chih-Man Chen, Chinpiao Yang, Jinn-Moon Liang, Mei-Chih Wong, Kwok-Kin Chao, Jui-I |
關鍵字: | Drug resistance; EGFR inhibitor; Non-small cell lung cancer; Survivin; Tumor growth | 公開日期: | 十一月-2021 | 卷: | 193 | 來源出版物: | Biochemical pharmacology | 摘要: | Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are currently used therapy for non-small cell lung cancer (NSCLC) patients; however, drug resistance during cancer treatment is a critical problem. Survivin is an anti-apoptosis protein, which promotes cell proliferation and tumor growth that highly expressed in various human cancers. Here, we show a novel synthetic compound derived from gefitinib, do-decyl-4-(4-(3-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)propyl) piper-azin-1-yl)-4-oxobutanoate, which is named as SP101 that inhibits survivin expression and tumor growth in both the EGFR-wild type and -T790M of NSCLC. SP101 blocked EGFR kinase activity and induced apoptosis in the A549 (EGFR-wild type) and H1975 (EGFR-T790M) lung cancer cells. SP101 reduced survivin proteins and increased active caspase 3 for inducing apoptosis. Ectopic expression of survivin by a survivin-expressed vector attenuated the SP101-induced cell death in lung cancer cells. Moreover, SP101 inhibited the gefitinib-resistant tumor growth in the xenograft human H1975 lung tumors of nude mice. SP101 substantially reduced survivin proteins but conversely elicited active caspase 3 proteins in tumor tissues. Besides, SP101 exerted anticancer abilities in the gefitinib resistant cancer cells separated from pleural effusion of a clinical lung cancer patient. Consistently, SP101 decreased the survivin proteins and the patient-derived xenografted lung tumor growth in nude mice. Anti-tumor ability of SP101 was also confirmed in the murine lung cancer model harboring EGFR T790M-L858R. Together, SP101 is a new EGFR inhibitor with inhibiting survivin that can be developed for treating EGFR wild-type and EGFR-mutational gefitinib-resistance in human lung cancers. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/639941 | ISSN: | 00062952 | DOI: | 10.1016/j.bcp.2021.114792 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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