Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53

Arya, Aditya; Elfert, Asem; Devling, Timothy; Eccles, Richard; Aslam, Mohammed Afeef; Rubbi, Carlos P.; Vlatković, Nikolina; Fenwick, John D.; Lloyd, Bryony H.; Sibson, D. Ross; Jones, Terence M.; Boyd, Mark T.

doi:10.1038/sj.bjc.6605739

Cited by 53 publications

(46 citation statements)

References 43 publications

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“…Nutlin-3 may sensitize wild-type TP53 ovarian cancer cell lines to cisplatin via multiple factors including increased p53-dependent apoptosis [33, 34]. Surprisingly, the combination of RG7388 with cisplatin showed no evidence of synergy for reduction of colony forming ability.…”

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

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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.

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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

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“…Lowering the apoptotic threshold was sufficient to switch the p53 cell fate from arrest to apoptosis, which has important implications for the effectiveness of p53-based cancer therapy .” Growth arrest in these experiments was judged from accumulation of cells in the G0/G1 phase of the cell cycle [41]. In other studies, nutlin-3-triggered activation of p53 signaling was shown to result in marginal apoptosis but a high degree of growth arrest through SIPS in p53 wild-type cancer cells [42,43,44,45]. …”

Section: Biological Outputs Orchestrated By Wild-type P53mentioning

confidence: 99%

Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome

Mirzayans

Andrais

Kumar

et al. 2017

IJMS

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Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or eliminate highly injured cells from the proliferating population. The wild-type p53 tumor suppressor and its downstream effector p21WAF1 (p21) are key regulators of these responses. Although extensively studied for its ability to control cell cycle progression, p21 has emerged as a multifunctional protein capable of downregulating p53, suppressing apoptosis, and orchestrating prolonged growth arrest through stress-induced premature senescence. Studies with solid tumors and solid tumor-derived cell lines have revealed that such growth-arrested cancer cells remain viable, secrete growth-promoting factors, and can give rise to progeny with stem-cell-like properties. This article provides an overview of the mechanisms by which p53 signaling suppresses apoptosis following genotoxic stress, facilitating repair of genomic injury under physiological conditions but having the potential to promote tumor regrowth in response to cancer chemotherapy.

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“…Nutlin-3 has been shown, alone or in combination with chemotherapeutic agents, to increase the degree of apoptosis in hematologic malignancies (13). Recent studies extended its therapeutic window for use in solid tumors (14,15).…”

Section: Introductionmentioning

confidence: 99%

Integrin α5β1 Plays a Critical Role in Resistance to Temozolomide by Interfering with the p53 Pathway in High-Grade Glioma

et al. 2012

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Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the a5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the a5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of a5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the a5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, a5b1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high a5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between a5b1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that a5b1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of a5b1 integrin. Cancer Res; 72(14); 3463-70. Ó2012 AACR.

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Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53

Cited by 53 publications

References 43 publications

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

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

Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome

Integrin α5β1 Plays a Critical Role in Resistance to Temozolomide by Interfering with the p53 Pathway in High-Grade Glioma

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