Targeting MDM2 for Neuroblastoma Therapy: In Vitro and In Vivo Anticancer Activity and Mechanism of Action

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.

Exosomal lncRNA CHL1-AS1 Derived from Peritoneal Macrophages Promotes the Progression of Endometriosis via the miR-610/MDM2 Axis

“…MDM2, which is located in segment 13–14 of the long arm of chromosome 12, is found in the double minute chromosome of the transformed murine cell line. 31 Accumulating evidence indicates that MDM2 can enhance cellular activity and promote tumor growth, 32 , 33 which could reveal a new therapeutic strategy for EMs. Previous studies indicated that the positivity rate of MDM2 expression in normal endometrium was lower than that in EMs, 34 , 35 which suggests that MDM2 serves as a promoting factor in EMs.…”

In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines

“…However, neuroblastoma seems not to be on that line of response: on the contrary, TP53 mutated alleles seem to increase apoptosis and stop the cell cycle without a prior need for wild-type p53 protein restoration. Not only patients with wild-type TP53 neuroblastoma, but also those with mutant TP53 neuroblastoma might have a good outlook if treated with inhibitors of MDM2 [80,81]. In any case, new strategies are needed to solve this issue, with an open look at the p53/MDM2 interaction, in order to clearly improve the prognosis in neuroblastoma patients.…”

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

“…92 Notably, MDM2 upregulation was observed in various cancers, bringing it a promising target for cancer treatment. 93,94 For instance, inactivating MDM2 suppressed HCC tumor proliferation and invasion and enhanced sensitivity to sorafenib. 95 Further, targeting MDM2-p53 interaction improved adaptive immunity in tumor cells with wild-type p53.…”