https://scholars.lib.ntu.edu.tw/handle/123456789/541946
Title: | MLN4924 synergistically enhances cisplatin-induced cytotoxicity via jnk and bcl-xl pathways in human urothelial carcinoma | Authors: | Ho I.-L. Kuo K.-L. Liu S.-H.-. HONG-CHIANG CHANG Hsieh J.-T. Wu J.-T. CHIH-KANG CHIANG WEI-CHOU LIN YU-CHIEH TSAI Chou C.-T. Hsu C.-H. YEONG-SHIAU PU Shi C.-S. KUO-HOW HUANG |
Issue Date: | 2015 | Publisher: | Nature Publishing Group | Journal Volume: | 5 | Start page/Pages: | 16948 | Source: | Scientific Reports | Abstract: | Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma. However, the response rate is only 40-65%. This study investigated the anti-tumor effect and underlying mechanisms of the combination of cisplatin and the NEDD8-activating enzyme inhibitor MLN4924 in human bladder urothelial carcinoma. The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index <1). MLN4924 also potentiated the cisplatin-induced apoptosis and activation of caspase-3 and -7, phospho-histone H2A.X and PARP. c-Jun N-terminal kinase (JNK) activation and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) were also observed during cisplatin and MLN4924 treatment. Inhibition of JNK activation partially restored cell viability and Bcl-xL expression. Bcl-xL overexpression also rescued cell viability. MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice. In summary, MLN4924 synergistically enhanced the anti-tumor effect of cisplatin via an increase in DNA damage, JNK activation and down-regulation of Bcl-xL in urothelial carcinoma cells. These findings provide a new therapeutic strategy for the treatment of bladder cancer. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84948388929&doi=10.1038%2fsrep16948&partnerID=40&md5=8fad9e7673211d2b46c07e00ad5a8dff https://scholars.lib.ntu.edu.tw/handle/123456789/541946 |
ISSN: | 2045-2322 | DOI: | 10.1038/srep16948 | SDG/Keyword: | ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulphamate; antineoplastic agent; BCL2L1 protein, human; CASP3 protein, human; CASP7 protein, human; caspase 3; caspase 7; cisplatin; cyclopentane derivative; drug combination; H2AFX protein, human; histone; mitogen activated protein kinase kinase 4; NEDD8 protein, human; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein bcl x; pyrimidine derivative; ubiquitin; animal; antagonists and inhibitors; apoptosis; cancer grading; Carcinoma, Transitional Cell; drug combination; drug effects; drug potentiation; drug screening; gene expression regulation; genetics; human; metabolism; mouse; nude mouse; pathology; signal transduction; tumor cell line; Urinary Bladder Neoplasms; Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Carcinoma, Transitional Cell; Caspase 3; Caspase 7; Cell Line, Tumor; Cisplatin; Cyclopentanes; Drug Combinations; Drug Synergism; Gene Expression Regulation, Neoplastic; Histones; Humans; MAP Kinase Kinase 4; Mice; Mice, Nude; Neoplasm Grading; Poly(ADP-ribose) Polymerases; Pyrimidines; Signal Transduction; Ubiquitins; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays |
Appears in Collections: | 醫學系 |
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