Oncotarget

Research Papers:

Second-generation proteasome inhibitor carfilzomib sensitizes neuroblastoma cells to doxorubicin-induced apoptosis

Shan Guan, Yanling Zhao, Jiaxiong Lu, Yang Yu, Wenjing Sun, Xinfang Mao, Zhenghu Chen, Xin Xu, Jessie Pan, Surong Sun _ and Jianhua Yang

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Oncotarget. 2016; 7:75914-75925. https://doi.org/10.18632/oncotarget.12427

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Abstract

Shan Guan1,2, Yanling Zhao2, Jiaxiong Lu2,3, Yang Yu2,4, Wenjing Sun2,4, Xinfang Mao1,2, Zhenghu Chen2,3, Xin Xu2, Jessie Pan2, Surong Sun1, Jianhua Yang2

1Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, Xinjiang, China

2Texas Children’s Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA

3Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

4Labratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, China

Correspondence to:

Surong Sun, email: sr_sun2005@163.com

Jianhua Yang, email: jianhuay@bcm.edu

Keywords: neuroblastoma, proteasome inhibitor, carfilzomib, chemotherapy, doxorubicin

Received: July 20, 2016    Accepted: September 22, 2016    Published: October 04, 2016

ABSTRACT

Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common extracranial malignant neoplasm in children. Elevated level of proteasome activity promotes cancer development and the inhibition of proteasome activity is a promising strategy for cancer treatment. Therefore, targeting proteasome by small molecule inhibitors may be a viable option for NB therapy. Here in this study, we show that a novel proteasome inhibitor Carfilzomib (CFZ) exerts anti-tumor effect on NB. CFZ caused decreased cell viability and attenuated colony formation ability of a subset of NB cell lines. CFZ induced cell apoptosis in NB cells. Moreover, CFZ enhanced the cytotoxic effect of doxorubicin (Dox) on NB cells and Dox-induced p38 and JNK phosphorylation. In addition, CFZ inhibited Dox-induced NF-κB activation by stabilizing the protein level of IκBα. Furthermore, CFZ induced apoptosis and augmented Dox-induced apoptosis in NB tumor cells in orthotopic xenograft mouse models. In summary, our study suggests that proteasome is a therapeutic target in NB and proteasome inhibition by CFZ is a potential therapeutic strategy for treating NB patients.


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