MLN4924, a Novel NEDD8-activating enzyme inhibitor, exhibits antitumor activity and enhances cisplatin-induced cytotoxicity in human cervical carcinoma: In vitro and in vivo study
Journal
American Journal of Cancer Research
Journal Volume
5
Journal Issue
11
Pages
3350-3362
Date Issued
2015
Author(s)
Kuo K.-L.
Shi C.-S.
Wu J.-T.
Hsieh J.-T.
Liao S.-M.
Chou C.-T.
Chiu W.-S.
Chiu T.-Y.
Ho I.-L.
Wang Z.-H.
Chang S.-C.
Abstract
MLN4924, an inhibitor of NEDD8 activating enzyme (NAE), has been reported to have activity against various malignancies. Here, we investigated the antitumor properties of MLN4924 and MLN4924 in combination with cisplatin on human cervical carcinoma (CC) in vitro and in vivo. Two human CC cell lines, ME-180 and HeLa, were used in this study. The cytotoxic effects of MLN4924 and/or cisplatin were measured by cell viability (MTT), proliferation (BrdU incorporation), apoptosis (flow cytometry with annexin V-FITC labeling), and the expression of cell apoptosis-related proteins (Western blotting). In vivo efficacy was determined in Nu/Nu nude mice with ME-180 and HeLa xenografts. The results showed that MLN4924 elicited viability inhibition, anti-proliferation and apoptosis in human CC cells, accompanied by activations of apoptosis-related molecules and Bid, Bcl-2 phosphorylation interruption, and interference with cell cycle regulators. Moreover, MLN4924 caused an endoplasmic reticulum stress response (caspase-4, ATF-4 and CHOP activations) and expression of other cellular stress molecules (JNK and c-Jun activations). Additionally, MLN4924 suppressed growth of CC xenografts in nude mice. Furthermore, we demonstrated that MLN4924 potentiated cisplatin-induced cytotoxicity in CC cells with activation of caspases. Consistently with this, MLN4924 significantly enhanced cisplatin-induced growth inhibition of CC xenografts. Together, these findings suggest that MLN4924 alone or in combination with cisplatin is of value in treating human CCs.
SDGs
Other Subjects
activating transcription factor 4; caspase 4; cisplatin; growth arrest and DNA damage inducible protein 153; Janus kinase; pevonedistat; protein bcl 2; protein Bid; protein c jun; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; Article; cancer combination chemotherapy; cell proliferation; cell survival; cell viability; controlled study; drug cytotoxicity; drug effect; endoplasmic reticulum stress; female; human; human cell; in vitro study; in vivo study; mouse; neddylation; nonhuman; protein phosphorylation; tumor volume; uterine cervix carcinoma
Publisher
E-Century Publishing Corporation
Type
journal article