Table 1.
Overview of single or combined GB treatment strategies with MDM2/X inhibitors.
| Treatment | Type | C/PC | GB in vitro / in vivo model | Results | Reference | |
|---|---|---|---|---|---|---|
| MDM2/X inhibition combined with irradiation | ||||||
| MDM2 - RT | Nutlin-3 + X-rays (0, 2, 4, 6, 8 Gy) | SM | PC | U87MG wt, T98G mut | Varying levels of apoptosis and senescence and an enhanced radiosensitivity among the different p53 wt GB cell lines. GB cell lines with mutated or knockdown p53 were completely unresponsive to the drug | (142) |
| Resveratrol + X-rays (2, 4, 6 Gy) | Na | PC | SU-2 GSCs | Radiosentizing effect on GSCs. The combination has synergistic antitumor properties like blockade of proliferation, triggering of autophagy, facilitation of apoptosis as well as preclusion of DNA repair | (145) | |
| RG7388£ | SM | C | GB patients with an unmethylated MGMT promoter | Included in active N²M² (NOA-20) trial in in conjunction with RT | NCT03158389 (54) | |
|
PC |
||||||
| U87MG wt | Combination with RT showed inhibited clonogenicity. Induced cell cycle arrest and apoptosis. However, long-term treatment induces resistance to treatment (2Gy and 4Gy) | (29) | ||||
| Targeting the MDM2-p53 interaction | ||||||
| Nutlins | Nutlin-3a | SM | PC | NOD.Cg-PrkdcscidIL2rgtm1Wjl/Sz (NSG) mice | Three cycles of TMZ/nutlin3a resulted in a significant survival increase of the GB10 intracranial in vivo model compared with single therapy | (146) |
| RG7112 | SM | PC | SJ-GBM2, GBM2, BT-39, D645, D456, CB17SC scid -/- female mice | Reduced tumor growth in GB PPTP& models in vitro and in vivo | (23) | |
| PC | U373MG mut, LN18 mut, U251MG mut, A120wt T, DBTRG-05MGwt, U87MG wt. | A greater sensitivity of wt cell lines were observed, while the mutant p53 cell lines showed resistance | (26) | |||
| PC | U251MG mut, U87MG wt LN229 mut | Restored p53 activity inducing strong p21 expression and apoptosis. PK profiling demonstrated crossing of the BBB. Cytotoxicity was observed, but treatment reduced tumor growth and increased survival. | (147) | |||
| RG7388 | SM | C, PC | See£ | NCT03158389 (29) | ||
| Piperidinones | AMG232 (KRT-232) | SM | C | Recurrent or newly diagnosed GB | Included in active N²M² (NOA-20) trial in conjunction with RT and a phase I trial | NCT03158389 (54) |
| PC | U373 mut, LN18 mut, U251 mut, A1207wt, DBTRG-05MGwt, U87MG wt | 9.5-fold more effective than RG7112 in p53 wt GB cells | NCT03107780 (54) | |||
| 10 patient-derived GSCs | MDM2-amplified stem cells (464T) were 35-fold more sensitive to AMG232 | (148) | ||||
| 100 patient derived GB cell cultures, with computational modelling | Potentiated the effect of bortezomib in multiple GB cell lines by increasing apoptotic effects | (26) | ||||
| Spirooxindole Derivatives | ISA27 | SM | PC | U87MG wt | Synergy with TMZ: effective in inhibiting cell growth, to such an extent to possibly lower the dose of TMZ | (88) |
| Spiropyrazoline oxindole 1a | SM | PC | GL-261 | Treatment showed a decrease in SOX2 protein levels, thereby reducing stemness. In addition, chemotherapy sensitization in combination with TMZ was observed | (149) | |
| MI77301 (SAR405838) | SM | PC | PDX models of GB | A sensitivity was observed in MDM2-amplified PDX lines with high MDM2 expression in comparison to MDM2 control lines in both in vitro and heterotopic models. Contradictory results for orthotopic tumors: inefficiency | (28) | |
| Other | MK-8242 (formerly SCH 900242) | SM | PC | PPTP& cell line panel including GB cell lines SJ-GBM2, GBM2, BT-39, D645, D456 | Cell lines with wt TP53 showed a sensitivity, while a resistance for cell lines with mut TP53 was observed. Results showed a reduction in tumor growth for most of the PPTP& panel as well as the xenograft models | (25) |
| Other approaches to enhance p53 activity in GB | ||||||
| Blocking MDM2 expression | SP-141 | SM | PC | U87MG, SNB19, U251, LN229, T98G, GBM10, SF188, UW18 and UW28 cell lines | Effectively induced cell cycle arrest and apoptosis. Effective antitumor activity against U87MG intracranial xenografts and combination treatment with TMZ resulted in more effective cell killing and suggested to aid in TMZ resistance | (146) |
| miR-129 | miRNA | PC | U251 mut and U87MG wt | rtPCR done on cell lines significantly reduced the expression of MDM2, resulting in cell cycle arrest | (150) | |
| miR-17 | miRNA | PC | U87MG wt | Repressed MDM2, resulting in decreased cell proliferation and drug resistance | (151) | |
| miR-4486 | miRNA | PC | Glioma cells - U87MG, U251, SHG-44, SW-38 | Down-regulation of MDM2 by miR-4486 increased the abundance of p53 in glioma cells | (152) | |
| Restoration p53 expression or active conformation | CP-31398 | SM | PC | LN-18, U138MG, U87MG, LN-428, D247MG, T98G, LN-319, LN-229, A172, U251MG, U373MG, LN-308 | p53 reporter gene activity in all of tested glioma cell lines harboring either wt or mut p53 was induced. All cell lines underwent a caspase-independent and bcl-xL-insensitive cell death after prolonged incubation | (153) |
| PRIMA-1 | SM | PC | Multiple p53 mut GB cell lines | Despite showing selective single agent activity in p53 mut cells, it did not increase bortezomib activity | (154) | |
| GB mouse models | Restores p53 wt conformation by altering p53 mut protein folding - inhibition of cell growth and stemness as well as apoptosis induction | (19) | ||||
| NSC319726 | SM | PC | GB patient derived cells | Induces copper-dependent cell cycle arrest at picomolar concentrations | (155) | |
| RITA | SM | PC | U251 mut and U87MG wt | Inhibited proliferation of p53 mut U251 more effectively than p53 wt U87MG GB cell lines | (156) | |
| P53R3 | SM | PC | T98G, U251, U373MG, U138MG, LNT-229 | Restored p53 expression and induced antiproliferative effects, resulting in a higher apoptotic induction rate | (157) | |
| p53p-Ant | P | PC | Human: U138, U87MG, Rat: 9L, D74, F98, NL | A 3-fold increase in extracellular membrane Fas expression, resulting in activation of p53 function and consequently induction of apoptosis in both p53 mut and wt cell lines | (158) | |
| SGT-53 gene therapy | Nanocomplex that delivers p53 wt | PC | GL261 | Enhanced anti-tumor effects and reduced tumor cell proliferation | (159) | |
| Retroviral-mediated gene transfer | GT | PC | U87MG wt | Retroviral-mediated gene transfer of the p53 (175H) mut promotes apoptosis in association with adenoviral-mediated p53 wt gene transfer | (160) | |
| CRAd#AdDelta24-p53 + RT | GT (adenovirus) | PC | glioma cells in vitro and in vivo | Combination of RT and AdDelta24-p53 caused an increase in apoptosis. In vivo, combination therapy increased tumor regression and long-term survival | (161) | |
| p53-NLS-Ln-11R% | P | PC | glioma cells – YKG1 mut, T98G mut, U87MG wt | This protein-transduction method inhibited the proliferation of human glioma cells, whether the p53 gene had mutated or not | (162) | |
| Influencing MDM2-proteasome interaction | JNJ-26854165 (Serdematan) | SM | PC | SJ-GBM2 | Shows activity against both p53 wt and p53 mut cell lines and xenografts, including GB | (163) |
| Inhibition of the E3 ubiquitin ligase activity of MDM2 | USP2a | Ubiquitin-specific protease 2a | PC | U87MG wt | Results suggest that USP2a binds to and stabilizes MDMX, with subsequent higher mitochondrial localization of p53 and apoptosis | (164) |
| Natural compounds | Curcumin | Na | PC | SH-SY5Y neuroblastoma | Inhibits cell growth, arrests cells at S phase and induces apoptosis by decreasing the MDM2 protein level | (165) |
| U87MG wt xenograft | Increased cell death, reduced cell growth and inhibited migration and invasiveness | (166) | ||||
| U251 | Inhibited cell growth and induced G2/M and S-phase arrest in a dose dependent manner | (167) | ||||
| Flavopiridol | Na | PC | A172, CCF-STTG1, T98G, U87MG, U118MG, U251MG, and U373MG | Inhibited cell growth, arrested cells at G2/M phase and induced apoptosis by decreasing the MDM2 expression at mRNA level | (168) | |
| Chalcone | Na | PC | U87MG wt cells and xenograft | Inhibits cell growth, arrested cells at G1 phase and induces apoptosis by decreasing the MDM2 protein level. Inhibited tumor growth in U87MG xenograft mouse model | (165) | |
| Resveratrol | Na | PC | U87MG wt cells | Activates transcription of downstream p53 targeted genes, which leads to a decreased affinity for MDM2, causing an increase in p53 stability and thereby cell cycle arrest and apoptosis | (144) | |
| Dual MDM2/MDMX inhibitors | ||||||
| Peptide based MDM2/MDMX inhibitors | D-PMI-beta | P | PC | U251 mut and U87MG wt | Works in a p53-dependent manner as U251 mutated cells were resistant to treatment and successful growth inhibition was observed in U87MG wt cell lines | (97) |
| liposome-PMI1-4 | P | PC | U87MG wt and U251 | PMI failed to inhibit cell growth through MDM2/MDMX targeting. Peptide-loaded liposomes were designed to improve cellular uptake of the drug. Liposome-PMI-1 was the most effective in inducing apoptosis of U87MG cells, but not U251, indicating a p53 dependent interaction | (169) | |
| PM2 | P | PC | 4-10 GB cell lines | Potentiated the effect of the protease inhibitor bortezomib in multiple GB cell lines by effectively inducing cell death after treatment | (154) | |
| RGD-M/sPM€ | RGD-peptide micelle | PC | U251 mut and U87MG wt | RGD-liposomal pDP treatment increased the median survival time of intracranial U87MG GB nude mice. Western blot assay validated the reactivation of p53 through MDM2 inhibition in both cell lines | (170) | |
| Other | NSC623731 | SM | PC | U87MG wt | Demonstrated to possess anti-proliferative activity | (171) |
| MDM2/X inhibition and other combined treatment strategies | ||||||
| MDM2-chemotherapy | Nutlin-3a + Doxorubicin | SM | PC | U87MG wt | Treatment resulted in the reactivation of the p53 pathway, leading to an increase in p53 activity and consequently sensitization of the GB cells | (172) |
| Spiropyrazoline oxindole 1a + TMZ | SM | PC | GL-261 | Chemotherapy sensitization in combination with TMZ | (149) | |
| RITA + TMZ | SM | PC | U251 mut and U87MG wt | Inhibited proliferation of p53 mut U251 more effectively than p53 wt U87MG GB cell lines. In both instances, apoptosis was induced more effectively in combination with TMZ | (156) | |
| RGD-M/sPM€ + TMZ | RGD-peptide micelle | PC | U87MG wt | Anti-glioma effect through activation of the p53 pathway in vitro and in vivo. Synergistic with TMZ | (170) | |
| Resveratrol + TMZ | Na | PC | Human GB-initiating cells | Enhanced the sensitivity to TMZ via activation of the DSB/ATM/ATR/p53 pathway, leading to the activation of apoptosis | (173) | |
| RG7112 siRNA | SM siRNA | PC | U87MG wt cells and in vivo DK-MG (p53 wt), LN308 (p53 null), and U251 (p53 mut) | Enhanced the sensitivity to TMZ, reversing the YB-1 protein mediated TMZ drug resistance | (174) | |
| MDM2-integrins | Compound 9 | Pe | PC | U87MG wt cells | Effective in inducing long term cell cycle and proliferation arrest of GB cells by targeting MDM2/X as well as α5β1/αvβ3 integrins | (175) |
| MDM2-Akt/mTOR | FC85 +ISA27 | SM | PC | U87MG wt cells | Synergic effect on the inhibition of cell viability and on the reactivation of p53 pathway. Also blocked proliferation and promoted the differentiation of GSCs | (176) |
| MDM2-CDK4 | Ent-4g* | S | PC | T98G mut, U251 mut, U87MG wt | Induced apoptosis and cell cycle arrest. Cells treated showed up-regulation of proteins involved in P53 and cell cycle pathways. Anti-tumor efficacy against GB xenografts in mice | (177) |
| MDM2-MEK | RG7388 + Trametinib | SM | PC | U87MG, A172, T98G, LN428, LN308 and LN229; Xenograft mouse model | Clonogenicity synergistically inhibited through the combination, resulting in a restored sensitivity towards RG7388 in U87MG and A172 cell lines. In vivo, results demonstrated a reduction of tumor growth | (29) |
| MDM2/X-CXCRX | RS3594 + AMD3100 | SM | PC | Human GB cells and GB stem-like cells (neurospheres) U87MG, T98G, U343MG | Reduced GB cell invasiveness and migration in single agent treatment but this increased in the combined treatment regimen with synergic effects on cancer stem components. | (178) |
| MDM2/V-ATPase | Nutlin-3a + V-ATPase inhibitor (archazolid) | SM | PC | U87MG wt | Synergistic for inducing cell death in different p53 wt tumor cell lines and highly activated pro‐apoptotic pathways. Combination is more efficient in reducing tumor growth compared to single treatment in vivo | (179) |
| Other | p19Arf gene transfer and nutlin-3 | SM | PC | C6 wt GB cell line | C6 cells were quite susceptible to both, yet p53 was further activated by the combination. Results showed a marked increase in cell cycle alterations and an increase in p53 activity, thereby resulting in cell death | (180) |
ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad-3 related (ATR), BBB (blood brain barrier), BTSC (patient-derived brain tumor stem cell), C (clinical study), DSB (DNA double strand break), GSC (glioma stem cells), GT (gene transfer), MGMT [O(6)-methylguanine-DNA methyltransferase], P (Peptides), PC (pre-clinical study), PDX (patient-derived xenograft), Pe (Peptidomimetics), S (spirooxindoles), (Pi) Piperidones, miR (microRNA), Na (Natural compounds), NSG (NOD scid gamma mouse), SM (small molecule), RT (radiation therapy), TMZ (temozolomide), €RGD-M/sPMI [cyclic RGD peptide-conjugated poly (ethylene glycol)-co-poly (lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI)], &Pediatric preclinical testing program (PPTP), %p53-NLS-Ln-11R (polyarginine11R as a PTD, nuclear localization sequence (NLS), and laminin (Ln) fused to the p53 peptide corresponding to the MDM2 binding site), #conditionally replicating adenovirus (CRAd), *tetrahydronaphthalene fused spirooxindol.