Targeting MDM2 for neuroblastoma therapy: In vitro and in vivo anticancer activity and mechanism of action

Wei Wang, Xinjie Wang, Mehrdad Rajaei, Ji Youn Youn, Atif Zafar, Hemantkumar Deokar, John K. Buolamwini, Jianhua Yang, Jennifer H. Foster, Jia Zhou, Ruiwen Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Neuroblastoma is an aggressive pediatric solid tumor with an overall survival rate of <50% for patients with high-risk disease. The majority (>98%) of pathologically-diagnosed neuroblastomas have wild-type p53 with intact functional activity. However, the mouse double minute 2 (MDM2) homolog, an E3 ubiquitin ligase, is overexpressed in neuroblastoma and leads to inhibition of p53. MDM2 also exerts p53-independent oncogenic functions. Thus, MDM2 seems to be an attractive target for the reactivation of p53 and attenuation of oncogenic activity in neuroblastoma. Methods: In this study, we evaluated the anticancer activities and underlying mechanisms of action of SP141, a first-in-class MDM2 inhibitor, in neuroblastoma cell lines with different p53 backgrounds. The findings were confirmed in mouse xenograft models of neuroblastoma. Results: We demonstrate that SP141 reduces neuroblastoma cell viability, induces apoptosis, arrests cells at the G2/M phase, and prevents cell migration, independent of p53. In addition, in neuroblastoma xenograft models, SP141 inhibited MDM2 expression and suppressed tumor growth without any host toxicity at the effective dose. Conclusions: MDM2 inhibition by SP141 results in the inhibition of neuroblastoma growth and metastasis, regardless of the p53 status of the cells and tumors. These findings provide proof-of-concept that SP141 represents a novel treatment option for both p53 wild-type and p53 null neuroblastoma.

Original languageEnglish (US)
Article number3651
Pages (from-to)1-16
Number of pages16
JournalCancers
Volume12
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • Malignancies
  • MDM2
  • Metastasis
  • Neuroblastoma
  • P53
  • SP141

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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