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

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.

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

“…Simultaneous reactivation of p53 and TSPO proteins appears to be more effective in promoting apoptosis in GBMs cells but also in reducing the risk of resistance [ 238 ]. Reactivating these proteins using molecules with irreversible action has been suggested in order to reduce the risk of recurrence [ 239 ].…”

Targeted therapy based on p53 reactivation reduces both glioblastoma cell growth and resistance to temozolomide

“…To date, different other compounds targeting the MDM2-p53 interaction have been designed, which have proven to be promising also for GB treatment (27)(28)(29)(30)(31)(32)(33)(35)(36)(37)(38)(39). In this study, we compared the anti-proliferative effects of RITA with those of the well-known p53 re-activating molecule, nutlin-3, and observed that nutlin-3 was much less effective on GB cell lines under our experimental conditions, significantly reducing only the viability of the p53 wild-type cell lines (U-87MG and PRT-HU2) at the highest concentration.…”

“…Owing to its crucial role in apoptosis and cell growth control, and considering that its pathway is altered in the majority of human cancers (19), p53 represents one of the most appealing targets for cancer therapy and therefore, to date, several strategies targeting p53 and its pathway have been developed (20)(21)(22). Approaches aimed at restoring the oncosuppressive function of p53, through either wild-type TP53 gene transfer systems (12,23,24) or small molecule/peptide-based methods (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), have proven promising for GB treatment, owing not only to their pro-apoptotic and anti-proliferative effects, but also to their ability to sensitize GB cells to TMZ (23,24,28,30,33,37).…”

Exploiting the Indole Scaffold to Design Compounds Binding to Different Pharmacological Targets

“…As a continuation of our studies on 2-phenylindol-3-ylglyoxylyldipeptides 20, we synthesized 21, bearing a chemo-reactive isothiocyanate group at the 5-position of the indole nucleus. This compound, thanks to its ability to form covalent bonds with electrophilic groups, displayed a potent long-lasting binding affinity for TSPO and a prolonged inhibition of the MDM2-p53 complex [97]. Furthermore, 21 caused GBM cell death by arresting the cell cycle and inducing apoptosis; both effects were greater and more long-lasting than those of the reversible analogues of series 20.…”

“…Furthermore, 21 caused GBM cell death by arresting the cell cycle and inducing apoptosis; both effects were greater and more long-lasting than those of the reversible analogues of series 20. The observed apoptotic effects were irreversible so that the cells were not able to regain proliferative activity after drug wash-out [97].…”