Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells

Abstract

The poor prognosis of Glioblastoma Multiforme (GBM) is due to a high resistance to conventional treatments and to the presence of a subpopulation of glioma stem cells (GSCs). Combination therapies targeting survival/self-renewal signals of GBM and GSCs are emerging as useful tools to improve GBM treatment. In this context, the hyperactivated AKT/mammalian target of the rapamycin (AKT/mTOR) and the inhibited wild-type p53 appear to be good candidates. Herein, the interaction between these pathways was investigated, using the novel AKT/mTOR inhibitor FC85 and ISA27, which re-activates p53 functionality by blocking its endogenous inhibitor murine double minute 2 homologue (MDM2). In GBM cells, FC85 efficiently inhibited AKT/mTOR signalling and reactivated p53 functionality, triggering cellular apoptosis. The combined therapy with ISA27 produced a synergic effect on the inhibition of cell viability and on the reactivation of p53 pathway. Most importantly, FC85 and ISA27 blocked proliferation and promoted the differentiation of GSCs. The simultaneous use of these compounds significantly enhanced GSC differentiation/apoptosis. These findings suggest that FC85 actively enhances the downstream p53 signalling and that a combination strategy aimed at inhibiting the AKT/mTOR pathway and re-activating p53 signalling is potentially effective in GBM and in GSCs.

Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins

“…Inhibition of these proteins, as well as MAPK/ERK, is critical for induction of apoptosis (12,51,52,101). Furthermore, other studies indicate that treatments with targeting of the Pi3K/Akt/mTOR pathway and the MAPK/ERK protein induce early and late apoptosis (102)(103)(104), as also obtained in the present study.…”

The Nootropic Drug Α-Glyceryl-Phosphoryl-Ethanolamine Exerts Neuroprotective Effects in Human Hippocampal Cells

“…As depicted in Figure 3 (panel a and b), the PL precursor strongly enhanced the conversion of LC3 I to LC3II, as demonstrated by the increase of the LC3 II/LC3 I ratio. To confirm these data, a western blot analysis of the autophagic protein p62 [22] was performed, using the mTOR inhibitor [23,24] everolimus as a positive control. GPE was proven to significantly augment p62 accumulation, even to a greater extent than everolimus (Figure 3c,d).…”

“…Adult hippocampal neurons were seeded in 6-multiwell plates (1 × 10 5 cells/well) and incubated with saline buffer (control cells) or 500 µM GPE for seven days. In selected experiments, the mTOR inhibitor everolimus (50 nM) was used as positive control of autophagy induction [23,24].…”

Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

“…Daniele et al [270] (2015) demonstrated that a combined inhibition of Mdm2 and Mdm2 stimulating the AKT/mTOR pathway using inhibitors ISA27 and FC85, respectively, enhanced glioblastoma multiforme (GBM) cell apoptosis and differentiation of CSCs. In MEFs, Wienken et al (2016) [271] demonstrated that efficient iPSC generation is dependent on Mdm2 in absence of p53.…”