A Novel Therapeutic Mechanism of Imipridones ONC201/ONC206 in MYCN-Amplified Neuroblastoma Cells via Differential Expression of Tumorigenic Proteins.

Sarra El-Soussi,Amanda-Rose Khater,Tamara Abou-Antoun,Jad Abdallah,Reine Hanna,Wassim Abou-Kheir,Hanna Semaan

doi:10.3389/fped.2021.693145

Abstract

Neuroblastoma is the most common extracranial nervous system tumor in children. It presents with a spectrum of clinical prognostic measures ranging from benign growths that regress spontaneously to highly malignant, treatment evasive tumors affiliated with increased mortality rates. MYCN amplification is commonly seen in high-risk neuroblastoma, rendering it highly malignant and recurrence prone. In our current study, we investigated the therapeutic potential of small molecule inducers of TRAIL, ONC201, and ONC206 in MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cell lines. Our results exhibit potent antitumor activity of ONC201 and ONC206 via a novel inhibition of EGF-induced L1CAM and PDGFRβ phosphorylation in both cell lines. Drug treatment significantly reduced cellular proliferation, viability, migration, invasion, tumorsphere formation potential, and increased apoptosis in both cell lines. The protein expression of tumorigenic NMYC, Sox-2, Oct-4, FABP5, and HMGA1 significantly decreased 48 h post-drug treatment, whereas cleaved PARP1/caspase-3 and γH2AX increased 72 h post-drug treatment, compared with vehicle-treated cells in the MYCN-amplified IMR-32 cell line. We are the first to report this novel differential protein expression after ONC201 or ONC206 treatment in human neuroblastoma cells, demonstrating an important multitarget effect which may yield added therapeutic benefits in treating this devastating childhood cancer.

Highlights

Neuroblastoma (NB) is the most common solid extracranial pediatric tumor that arises from neural crest origin
We previously reported on the PDGFRBinduced transactivation of EGFR in medulloblastoma [21, 22] and neuroblastoma [23] cells that was effectively abrogated with imatinib and sunitinib
Our studies demonstrate an interesting interconnection between tumorigenic pathways, namely, EGFR, PDGFR, and L1 cell adhesion molecule (L1CAM)

Summary

Introduction

Neuroblastoma (NB) is the most common solid extracranial pediatric tumor that arises from neural crest origin. Despite the relatively low incidence, NB accounts for almost 15% of all childhood cancer deaths, pointing out to the poor prognosis of the disease [5].

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