MLN4924 synergistically enhances cisplatin-induced cytotoxicity via jnk and bcl-xl pathways in human urothelial carcinoma
Journal
Scientific Reports
Journal Volume
5
Pages
16948
Date Issued
2015
Author(s)
Ho I.-L.
Kuo K.-L.
Liu S.-H.-.
Hsieh J.-T.
Wu J.-T.
Chou C.-T.
Hsu C.-H.
Shi C.-S.
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.
SDGs
Other Subjects
((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
Publisher
Nature Publishing Group
Type
journal article