MLN4924 Synergistically Enhances Cisplatin-induced Cytotoxicity via JNK and Bcl-xL Pathways in Human Urothelial Carcinoma.

I-Lin Ho,June-Tai Wu,Wei-Chou Lin,Yu-Chieh Tsai,Shing-Hwa- Liu,Hong-Chiang Chang,Yeong-Shiau Pu,Chih-Kang Chiang,Kuo-How Huang,Kuan-Lin Kuo,Chen-Hsun Hsu,Chung-Sheng Shi,Chien-Tso Chou,Ju-Ton Hsieh

doi:10.1038/srep16948

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.

Highlights

Urinary bladder cancer is estimated to be the sixth most common cancer in the United States, with approximately 74,000 predicted new cases in 20151
Our results demonstrated that the combination of cisplatin and MLN4924 synergistically enhanced the cytotoxicity of cisplatin through increased DNA damage and Jun N-terminal kinase (JNK) activation and the down-regulation of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL) in vitro and in vivo
We previously reported that the treatment of human bladder urothelial carcinoma cells with MLN4924 significantly induced anti-tumor effects in vitro and in vivo, and MLN4924 exhibited minimal toxicity on normal urothelial cells[16]

Summary

Introduction

Urinary bladder cancer is estimated to be the sixth most common cancer in the United States, with approximately 74,000 predicted new cases in 20151. The standard therapy for metastatic bladder urothelial carcinoma is cisplatin-based chemotherapy[3], but the limited response rate because of chemoresistance and chemotherapy-related adverse effects mitigates its clinical efficacy[4]. Several new regimens and drugs are under investigation to improve the treatment of bladder urothelial carcinoma[5]. We hypothesized that a combination of cisplatin and MLN4924 would be a new strategy for the treatment of bladder urothelial carcinoma. Our results demonstrated that the combination of cisplatin and MLN4924 synergistically enhanced the cytotoxicity of cisplatin through increased DNA damage and JNK activation and the down-regulation of the anti-apoptotic protein Bcl-xL in vitro and in vivo. Our data suggest that the combination of cisplatin and MLN4924 is a high efficacy regimen for the clinical treatment of bladder urothelial carcinoma

Methods

Results

Conclusion