Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment.
Neuroblastoma (NB) is the most common extracranial malignant solid tumor seen in children and continues to lead to the death of many pediatric cancer patients. The poor outcome in high risk NB is largely attributed to the development of chemoresistant tumor cells. Doxorubicin (dox) has been widely employed as a potent anti-cancer agent in chemotherapeutic regimens; however, it also leads to chemoresistance in many cancer types including NB. Thus, developing novel small molecules that can overcome dox-induced chemoresistance is a promising strategy in cancer therapy. Here we show that the second generation proteasome inhibitor ixazomib (MLN9708) not only inhibits NB cell proliferation and induces apoptosis in vitro but also enhances dox-induced cytotoxicity in NB cells. Ixazomib inhibits dox-induced NF-κB activity and sensitizes NB cells to dox-induced apoptosis. More importantly, ixazomib demonstrated potent anti-tumor efficacy in vivo by enhancing dox-induced apoptosis in an orthotopic xenograft NB mouse model. Collectively, our study illustrates the anti-tumor efficacy of ixazomib in NB both alone and in combination with dox, suggesting that combination therapy including ixazomib with traditional therapeutic agents such as dox is a viable strategy that may achieve better outcomes for NB patients.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.|The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha 410008, P. R. China.|Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Haoyu
H
Li
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.|Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China.
Zhenghu
Z
Chen
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.|The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha 410008, P. R. China.|Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Ting
T
Hu
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Long
L
Wang
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Yang
Y
Yu
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Yanling
Y
Zhao
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Wenijing
W
Sun
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Shan
S
Guan
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jonathan C
JC
Pang
Division of Pediatric Surgery, Texas Children's Hospital Department of Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Sarah E
SE
Woodfield
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.|The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha 410008, P. R. China.
Qing
Q
Liu
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jianhua
J
Yang
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