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ABT-737, a BH3 mimetic, circumvents JNK-mediated upregulation of anti-apoptotic molecules in cisplatin-treated non-small cell lung cancer
DC Field | Value | Language |
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dc.contributor.author | 김은영 | - |
dc.date.accessioned | 2017-07-07T16:10:21Z | - |
dc.date.available | 2017-07-07T16:10:21Z | - |
dc.date.issued | 2015 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/148632 | - |
dc.description | 의과대학/박사 | - |
dc.description.abstract | A subset of non-small cell lung cancers (NSCLC), which do not have a druggable driver oncogene, are treated with cytotoxic chemotherapy, most commonly cisplatin, but clinical outcome is suboptimal. Tumors develop multiple resistance mechanisms and elevated levels of anti-apoptotic proteins triggered by a cisplatin-induced DNA damage response correlate with resistance. Here, we investigated the synergistic effects of a co-treatment with cisplatin and a BH3 mimetic, ABT-737, in both cell culture and in vivo NSCLC models. In A549 and H460 cells, there was a dose-dependent phosphorylation of Jun N-terminal kinase (JNK) by cisplatin treatment, followed by increased expression of anti-apoptotic molecules. Anisomycin, a JNK-specific activator, increased the mRNA levels of anti-apoptotic molecules and SP600125, JNK-inhibitor, suppressed their expression, suggesting that the elevation of the anti-apoptotic molecules was mediated by JNK. ABT-737 displaced BCL-xL from mitochondria to the cytoplasm and induced oligomerization of BAK. Furthermore, ABT-737 released cytochrome c from mitochondria. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a Lox-Stop-Lox (LSL) K-ras G12D mouse model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in a preclinical model, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC patients. | - |
dc.description.statementOfResponsibility | open | - |
dc.format | application/pdf | - |
dc.publisher | Graduate School, Yonsei University | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.title | ABT-737, a BH3 mimetic, circumvents JNK-mediated upregulation of anti-apoptotic molecules in cisplatin-treated non-small cell lung cancer | - |
dc.title.alternative | 비소세포폐암에서 BH3 유사 약물인 ABT-737과 cisplatin의 병용 투여로서 세포 고사 촉진을 통한 새로운 폐암 치료법 개발 | - |
dc.type | Thesis | - |
dc.contributor.department | Dept. of Internal Medicine (내과학교실) | - |
dc.contributor.localId | A00811 | - |
dc.contributor.alternativeName | kim, Eun Young | - |
dc.contributor.affiliatedAuthor | 김은영 | - |
dc.type.local | Dissertation | - |
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