Human Glioblastoma Multiforme: p53 Reactivation by a Novel MDM2 Inhibitor

Costa, Barbara; Bendinelli, S; Gabelloni, P; Pozzo, Eleonora Da; Daniele, Simona; Scatena, F.; Vanacore, Renato; Campiglia, Pietro; Bertamino, Alessia; Gómez-Monterrey, Isabel; Sorriento, Daniela; Giudice, Carmine Del; Iaccarino, Guido; Novellino, Ettore; Martini, Claudia

doi:10.1371/journal.pone.0072281

Cited by 68 publications

(145 citation statements)

References 42 publications

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…These MDM2-amplified GBM patients have a worse progression-free and total survival and decreased response to therapy [41]. In the subset of tumors with MDM2 amplification, MDM2 could potentially be targeted with inhibitor compounds, allowing the otherwise normal p53 to function [42][43][44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

et al. 2017

View full text Add to dashboard Cite

According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

show abstract

Section: Discussionmentioning

confidence: 99%

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Cell survival analysis was determined by conventional viability assays [46]. Specifically, cell number was determined using Trypan blue dye exclusion assay and Scepter 2.0 Automated Cell Counter (Millipore) as previously described [47].…”

Section: U87mg Cells After Treatment: Survival Analysismentioning

confidence: 99%

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

et al. 2014

Self Cite

View full text Add to dashboard Cite

Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO control on death/life processes in a standardized glioblastoma cell setting. After 90 min irDE-MPIGA cell treatment, 25 nM ligand concentration saturated irreversibly all TSPO binding sites; after 24 h, TSPO de-novo synthesis occurred and about 40 % TSPO binding sites resulted covalently bound to irDE-MPIGA. During cell culture treatments, several dynamic events were observed: (a) early apoptotic markers appeared, such as mitochondrial membrane potential collapse (at 3 h) and externalization of phosphatidylserine (at 6 h); (b) cell viability was reduced (at 6 h), without cell cycle arrest. After digitonin-permeabilized cell suspension treatment, a modulation of mitochondrial permeability transition pore was evidenced. Similar effects were elicited by the reversible TSPO ligand PIGA only when applied at micromolar dose. Interestingly, after 6 h, irDE-MPIGA cell exposure restored cell survival parameters. These results highlighted the ligand-target residence time and the cellular setting are crucial parameters that should be taken into account to understand the drug binding affinity and efficacy correlation and, above all, to translate efficiently cellular drug responses from bench to bedside.

show abstract

“…Similarly, in NETs, low MGMT expression [51,52] or MGMT promoter hypermethylation [97] is associated with a higher sensitivity to alkylating chemotherapeutics such as temozolomide. The MDM2 inhibitor ISA27 and temozolomide have been reported to exert synergistic antiproliferative effects on human glioblastoma multiforme [53] . Expression of p53 wild type has been reported to downregulate MGMT in glioblastoma [54][55][56][57] .…”

Section: Discussionmentioning

confidence: 99%

“…In human glioblastoma cells, the MDM2 inhibitor ISA27 and temozolomide have been reported to exert synergistic antiproliferative effects [53] , while expression of p53 wild type downregulates MGMT expression in glioblastoma [54][55][56][57] and sensitizes glioblastoma cells to temozolomide [58] . Therefore, we aimed to investigate whether there are additive effects of co-incubation with temozolomide and the MDM2 inhibitor NVP-CGM097 on the expression profile of MGMT.…”

Section: Got1 Tumor Cellsmentioning

confidence: 99%

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

et al. 2016

View full text Add to dashboard Cite

Background/Aims: The tumor suppressor p53 is depleted in many tumor cells by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) through MDM2/p53 interaction. A novel target for inhibiting p53 degradation and for causing reexpression of p53^{wild type} is inhibition of MDM2. The small molecule NVP-CGM097 is a novel MDM2 inhibitor. We investigated MDM2 inhibition as a target in neuroendocrine tumor cells in vitro. Methods: Human neuroendocrine tumor cell lines from the pancreas (BON1), lung (NCI-H727), and midgut (GOT1) were incubated with the MDM2 inhibitor NVP-CGM097 (Novartis) at concentrations from 4 to 2,500 nM. Results: While p53^{wild type} GOT1 cells were sensitive to NVP-CGM097, p53^mutated BON1 and p53^mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 ± 9.2% (p < 0.05), 77.4 ± 6.6% (p < 0.01), and 47.7 ± 9.2% (p < 0.01). In a Western blot analysis of GOT1 cells, NVP-CGM097 caused a dose-dependent increase in the expression of p53 and p21 tumor suppressor proteins and a decrease in phospho-Rb and E2F1. Experiments of co-incubation of NVP-CGM097 with 5-fluorouracil, temozolomide, or everolimus each showed additive antiproliferative effects in GOT1 cells. NVP-CGM097 and 5-fluorouracil increased p53 and p21 expression in an additive manner. Conclusions: MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53^{wild type}. Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.

show abstract

Human Glioblastoma Multiforme: p53 Reactivation by a Novel MDM2 Inhibitor

Cited by 68 publications

References 42 publications

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

Contact Info

Product

Resources

About