Combination therapy with p53–MDM2 binding inhibitors for malignancies

Jin, Zegao; Shen, Jianfeng; He, Jing-Yao; Hu, Chunqi

doi:10.1007/s00044-014-1089-7

Cited by 5 publications

(2 citation statements)

References 77 publications

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“…In particular, p53-Ser46 phosphorylation by kinase HIPK2 is able to neutralize MDM2-mediated p53 inhibition rescuing p53 transcriptional activity of pro-apoptotic factors such as p53AIP1 , PIG3 , Bax , Noxa , Puma and Killer/DR5 [ 138 – 142 ]. The interaction between p53 and MDM2 is a promising target in anticancer therapy [ 143 ]. To this aim, various peptidomimetic small molecules have been developed as protein-protein interaction blockers [ 144 ].…”

Section: Introductionmentioning

confidence: 99%

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Pistritto

Trisciuoglio²,

Ceci

et al. 2016

Aging

1,179

792

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Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed.

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Section: Introductionmentioning

confidence: 99%

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Pistritto

Trisciuoglio²,

Ceci

et al. 2016

Aging

1,179

792

View full text Add to dashboard Cite

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“…These highlight that the determinants of sensitivity to MDM2 inhibitors in a TP53 wild-type background are poorly understood. The use of combination regimens and patient stratification strategies are therefore being investigated to optimise tumour specific response in TP53 wild-type malignancies (11-13).…”

Section: Introductionmentioning

confidence: 99%

Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner

Esfandiari

Hawthorne

Nakjang

et al. 2016

Molecular Cancer Therapeutics

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Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 AE a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non-growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI 50 ). Potentiation also correlated with significant increase in MDM2 inhibitor-induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53Ser15 , known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53Ser15 and its potential use as a biomarker for response to this combination regimen. Mol Cancer Ther; 15(3); 379-91. Ó2016 AACR.

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Podophyllum derivatives containing fluorine atom in the 3-position of 2-aminopyridine improved the antitumor activity by inducing P53-dependent apoptosis

Huai

2017

Med Chem Res

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Combination therapy with p53–MDM2 binding inhibitors for malignancies

Cited by 5 publications

References 77 publications

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner

Podophyllum derivatives containing fluorine atom in the 3-position of 2-aminopyridine improved the antitumor activity by inducing P53-dependent apoptosis

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