Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma
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Jiaxiong Lu1,2, Shan Guan2, Yanling Zhao2, Yang Yu2,3, Yongfeng Wang2, Yonghua Shi4,5, Xinfang Mao2,6, Kristine L. Yang2, Wenjing Sun3, Xin Xu2, Joanna S. Yi2, Tianshu Yang1, Jianhua Yang1,2, Jed G. Nuchtern2,3
1Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
2Texas Children’s Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
3Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA
4Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
5Department of Pathology, Basic Medicine College of Xinjiang Medical University, Urumqi, Xinjiang 830011, China
6Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830046, China
TianshuYang, email: firstname.lastname@example.org
Jianhua Yang, email: email@example.com
Jed G. Nuchtern, email: firstname.lastname@example.org
Keywords: neuroblastoma, MDM2 inhibitor, SAR405838, chemo-resistance, chemotherapy
Received: May 02, 2016 Accepted: September 25, 2016 Published: October 13, 2016
Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common childhood extracranial malignant tumor. In NB, somatic mutations of the tumor suppressor, p53, are exceedingly rare. Unlike in adult tumors, the majority of p53 downstream functions are still intact in NB cells with wild-type p53. Thus, restoring p53 function by blocking its interaction with p53 suppressors such as MDM2 is a viable therapeutic strategy for NB treatment. Herein, we show that MDM2 inhibitor SAR405838 is a potent therapeutic drug for NB. SAR405838 caused significantly decreased cell viability of p53 wild-type NB cells and induced p53-mediated apoptosis, as well as augmenting the cytotoxic effects of doxorubicin (Dox). In an in vivo orthotopic NB mouse model, SAR405838 induced apoptosis in NB tumor cells. In summary, our data strongly suggest that MDM2-specific inhibitors like SAR405838 may serve not only as a stand-alone therapy, but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact MDM2-p53 axis.
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