Long lasting MDM2/Translocator protein modulator: a new strategy for irreversible apoptosis of human glioblastoma cells.

Simona Daniele,Maria L Trincavelli,Sabrina Taliani,Luciana Marinelli,Claudia Martini,Elisa Zappelli,Federico Da Settimo,Ettore Novellino,Elisabetta Barresi

doi:10.18632/oncotarget.6872

Abstract

The development of multi-target drugs and irreversible modulators of deregulated signalling proteins is the major challenge for improving glioblastoma multiforme (GBM) treatment. Reversible single-target drugs are not sufficient to sustain a therapeutic effect over time and may favour the activation of alternative signalling pathways and the onset of resistance phenomena. Thus, a multi-target compound that has a long-lasting mechanism of action might have a greater and longer life span of anti-proliferative activity. Recently, a dual-target indol-3ylglyoxyldipeptide derivative, designed to bind to the Translocator Protein (TSPO) and reactivate p53 function via dissociation from its physiological inhibitor, murine double minute 2 (MDM2), has been developed as a potent GBM pro-apoptotic agent. In this study, this derivative was chemically modified to irreversibly bind MDM2 and TSPO. The new compound elicited a TSPO-mediated mitochondrial membrane dissipation and restored p53 activity, triggering a long-lasting apoptosis of GBM cells. These effects were sustained over time, involved a stable activation of extracellular signal regulated kinases and were specifically observed in cancer cells, in which these protein kinases are deregulated. Dual-targeting and irreversible binding properties combined in the same molecule may represent a useful strategy to overcome the time-limited effects elicited by classical chemotherapies.

Highlights

Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma [1], is the most common and lethal primary brain tumour in adults [2], with a median survival of less than 2 years
The major limitations of the current antiproliferative therapies for glioblastoma multiforme (GBM) are related to the onset of drug resistance phenomena [5]
Results from both basic and clinical research have suggested that the development of irreversible agents [12, 19] and multitarget compounds [9] may lead to the discovery of novel therapeutic strategies for GBM and other types of solid tumours

Summary

Introduction

Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma [1], is the most common and lethal primary brain tumour in adults [2], with a median survival of less than 2 years. The prognosis of GBM patients remains poor because of the onset of drug resistance and tumour recurrence [4, 5]. Recent discoveries in molecular biology have shown that the aberration of different signalling pathways are involved in the pathogenesis of malignant gliomas and have allowed the identification of new targets for novel therapeutic approaches, including growth factor ligands, receptors, and intracellular downstream effectors [7]. Because these deregulated intracellular signalling pathways, including the PI3K/Akt/mammalian target of the rapamycin (mTOR) and the Ras/extracellular signalwww.impactjournals.com/oncotarget

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Conclusion