Work

Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma

Year: 2016

Type: article

Abstract: // Jiaxiong Lu 1, 2 , Shan Guan 2 , Yanling Zhao 2 , Yang Yu 2, 3 , Yongfeng Wang 2 , Yonghua Shi 4, 5 , Xinfang Mao 2, 6 , Kristine L. Yang 2 , Wenjing Sun 3 , Xin Xu 2 , Joanna S. Yi 2 , Tianshu Yang 1 , Jianhua Yang 1, 2 , Jed G. Nuchtern 2, 3 1 Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China 2 Texas Children’s Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA 3 Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA 4 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 5 Department of Pathology, Basic Medicine College of Xinjiang Medical University, Urumqi, Xinjiang 830011, China 6 Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830046, China Correspondence to: TianshuYang, email: [email protected] Jianhua Yang, email: [email protected] Jed G. Nuchtern, email: [email protected] Keywords: neuroblastoma, MDM2 inhibitor, SAR405838, chemo-resistance, chemotherapy Received: May 02, 2016 Accepted: September 25, 2016 Published: October 13, 2016 ABSTRACT 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.12634