Structurally diverse MDM2–p53 antagonists act as modulators of MDR-1 function in neuroblastoma

Chen, L; Zhao, Yan; Halliday, Gail; Berry, Philip; Rousseau, Raphaël F.; Middleton, Steven A.; Nichols, Gwen; Bello, Fabio Del; Piergentili, A.; Newell, David R.; Lunec, John; Tweddle, Deborah A.

doi:10.1038/bjc.2014.325

Cited by 35 publications

(31 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study has reported potent preclinical efficacy combining the MTORC1 inhibitor temsirolimus with idasanutlin in neuroblastoma preclinical models . Temozolomide has previously been reported to be a substrate of MDR‐1, which is expressed at high levels in both SHSY5Y and NB1691 cells and we have previously reported that at very high concentrations idasanutlin is able to modulate MDR‐1 function . Taken together, these provide potential mechanisms by which MDM2 antagonists enhance temozolomide mediated cytotoxicity, consistent with the observed efficacy of RO6839921 combined with temozolomide.…”

Section: Discussionsupporting

confidence: 82%

“…Tumours were disaggregated in Phosphosafe buffer (Merck Millipore) using the Medimachine with Medicons inserts (BD Biosciences, Oxford, UK) and Western analysis carried out as previously described . Human MIC‐1 assays were performed according to manufacturer's protocols (R&D Systems).…”

Section: Methodsmentioning

confidence: 99%

“…(BD Biosciences, Oxford, UK) and Western analysis carried out as previously described. 21 Human MIC-1 assays were performed according to manufacturer's protocols (R&D Systems). IHC was performed using validated protocols and the Ventana Benchmark Ultra automated system (Ventana Medical Systems, Inc, Tucson, AZ, USA) in the Cellular Pathology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UK.…”

Section: Orthotopic In Vivo Experimentsmentioning

confidence: 99%

See 2 more Smart Citations

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

Chen

Pastorino

Berry

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

High‐risk neuroblastoma, a predominantly TP53 wild‐type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography‐mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post‐treatment with maximal p53 pathway activation 3–6 h post‐treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y‐Luc and NB1691‐Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Orthotopic In Vivo Experimentsmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

Chen

Pastorino

Berry

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…A possible explanation for this range of responses between the wild-type TP53 cell lines might be due to differences in drug uptake [30] or deficiencies or variation in the expression of p53 target genes involved in apoptosis and other mechanisms of cell death, including the pro-apoptotic proteins BAX and PUMA and anti-apoptotic proteins BCL-2 and MCL-1 [31, 32]. …”

Section: Discussionmentioning

confidence: 99%

Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer

2016

View full text Add to dashboard Cite

Ovarian cancer is the fifth leading cause of cancer-related female deaths. Due to serious side effects, relapse and resistance to standard chemotherapy, better and more targeted approaches are required. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies, non-genotoxic activation of wild-type p53 by small molecule inhibition of the MDM2-p53 binding interaction is a promising therapeutic strategy. Proof of concept was established with the cis-imidazoline Nutlin-3, leading to the development of RG7388 and other compounds currently in early phase clinical trials. This preclinical study evaluated the effect of Nutlin-3 and RG7388 as single agents and in combination with cisplatin in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3 or RG7388 combination with cisplatin was additive to, or synergistic in a p53-dependent manner, resulting in increased p53 activation, cell cycle arrest and apoptosis, associated with increased p21WAF1 protein and/or caspase-3/7 activity compared to cisplatin alone. Although MDM2 inhibition activated the expression of p53-dependent DNA repair genes, the growth inhibitory and pro-apoptotic effects of p53 dominated the response. These data indicate that combination treatment with MDM2 inhibitors and cisplatin has synergistic potential for the treatment of ovarian cancer, dependent on cell genotype.

show abstract

“…No reduction in cell viability was observed at concentrations up to 400 µg mL −1 (48 µg mL −1 quercetin concentration) when dex‐ald‐qcn‐12% was tested in nonmalignant cells (MRC‐5), demonstrating a good therapeutic window for this conjugate. Cisplatin is commonly used in the treatment of neuroblastoma and has reported IC 50 values for 72 h incubation in SH‐SY5Y and BE(2)‐C neuroblastoma cells of 0.2 to 0.4 µg mL −1 and 2.1 µg mL −1 , respectively. While these results are lower than the IC 50 of our conjugate (14.8 and 45.6 µg mL −1 quercetin, respectively), in contrast to dex‐ald‐qcn‐12%, cisplatin also shows considerable cytotoxicity toward nonmalignant MRC‐5 cells (IC 50 2.1–2.9 µg mL −1 ).…”

Section: Evaluation Of Anticancer Activitymentioning

confidence: 99%

Water Soluble Antioxidant Dextran–Quercetin Conjugate with Potential Anticancer Properties

Oliver

Yee

Kavallaris

et al. 2018

Macromolecular Bioscience

View full text Add to dashboard Cite

Quercetin, a naturally occurring potent antioxidant, is limited in therapeutic use, owing to its poor water solubility and stability. Herein, a method of conjugating quercetin to an aldehyde functionalized dextran via an HCl catalyzed condensation reaction to yield a water soluble quercetin functionalized polymer is reported. The prepared conjugate is characterized by H and H- C heteronuclear single quantum correlation (HSQC) NMR, which demonstrate that conjugation occurs via both the A- and B-rings of quercetin. The degree of quercetin functionalization can be tuned by varying the reaction temperature and/or the concentration of the HCl catalyst. However, as temperatures and HCl concentrations are increased above 40 °C and 2 m, respectively, the increase in functionalization is accompanied by an increase in the oxidation of the conjugated quercetin and a decrease in polymer yield. The prepared conjugate is shown to have improved stability compared with native quercetin while maintaining substantial free-radical scavenging activity. Anticancer activity is evaluated in vitro in a neuroblastoma cell line. The dextran-aldehyde-quercetin conjugate prepared at 40 °C and 2 m HCl is shown to be cytotoxic to neuroblastoma cells (SH-SY5Y-IC = 123 µg mL and BE(2)-C-IC = 380 µg mL ) but shows no activity against nonmalignant MRC-5 cells at concentrations up to 400 µg mL .

show abstract

Structurally diverse MDM2–p53 antagonists act as modulators of MDR-1 function in neuroblastoma

Cited by 35 publications

References 39 publications

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer

Water Soluble Antioxidant Dextran–Quercetin Conjugate with Potential Anticancer Properties

Contact Info

Product

Resources

About