ONC201/TIC10 Is Empowered by 2-Deoxyglucose and Causes Metabolic Reprogramming in Medulloblastoma Cells in Vitro Independent of C-Myc Expression.

Annika Dwucet,Georg Karpel-Massler,Qiyu Cao,Mike-Andrew Westhoff,Aurelia Peraud,Maximilian Pruss,Markus D Siegelin,Joshua E Allen,Varun V Prabhu,Mine Tanriover,Christian Rainer Wirtz

doi:10.3389/fcell.2021.734699

Abstract

The purpose of this study was to examine whether the imipridone ONC201/TIC10 affects the metabolic and proliferative activity of medulloblastoma cells in vitro. Preclinical drug testing including extracellular flux analyses (agilent seahorse), MTT assays and Western blot analyses were performed in high and low c-myc-expressing medulloblastoma cells. Our data show that treatment with the imipridone ONC201/TIC10 leads to a significant inihibitory effect on the cellular viability of different medulloblastoma cells independent of c-myc expression. This effect is enhanced by glucose starvation. While ONC201/TIC10 decreases the oxidative consumption rates in D458 (c-myc high) and DAOY (c-myc low) cells extracellular acidification rates experienced an increase in D458 and a decrease in DAOY cells. Combined treatment with ONC201/TIC10 and the glycolysis inhibitor 2-Deoxyglucose led to a synergistic inhibitory effect on the cellular viability of medulloblastoma cells including spheroid models. In conclusion, our data suggest that ONC201/TIC10 has a profound anti-proliferative activity against medulloblastoma cells independent of c-myc expression. Metabolic targeting of medulloblastoma cells by ONC201/TIC10 can be significantly enhanced by an additional treatment with the glycolysis inhibitor 2-Deoxyglucose. Further investigations are warranted.

Highlights

Medulloblastoma represents a heterogenous tumor entity that constitutes more than 60% of embryonal brain tumors in children (Khanna et al, 2017; Northcott et al, 2019)
We sought to examine whether ONC201/TIC10 has the ability to inhibit the cellular viability of medulloblastoma cells expressing varying levels of c-myc
D425, metastatic D458, DAOY, and HD-MB03 medulloblastoma cell lines as well as MB-PC322 primary cultured medulloblastoma cells were treated with increasing concentrations of ONC201/TIC10 prior to performing MTT assays (Figures 1A–E)

Summary

Introduction

Medulloblastoma represents a heterogenous tumor entity that constitutes more than 60% of embryonal brain tumors in children (Khanna et al, 2017; Northcott et al, 2019). This disease is mostly localized in the cerebellum and the majority of medulloblastomas occur in pediatric patients with a median age of 9 years (Roberts et al, 1991; Orr, 2020). Patients with group 3 myc-amplified or myc-overexpressing tumors were identified to be of high-risk facing a worse clinical outcome (Cavalli et al, 2017; Northcott et al, 2019). Novel strategies need to be developed that are taking in account the characteristics of the individual disease in order to increase the therapeutic efficacy and to lower the toxicity

Objectives

Results

Conclusion