Efficient Reactivation of p53 in Cancer Cells by a Dual MdmX/Mdm2 Inhibitor

Qin, Lingyun; Yang, Fei; Zhou, Cindy Ke; Chen, Yao; Zhang, Hua‐Shan; Su, Zhengding

doi:10.1021/ja509223m

Cited by 20 publications

(18 citation statements)

References 33 publications

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“…Nutlins and further MDM2 antagonists have been described as potent inducers of cell cycle arrest and apoptosis in several preclinical cancer models [39,[57][58][59][60] and have entered clinical trials. We conclude that nutlin-mediated MDM2 antagonism can induce both cell cycle arrest and apoptosis in GEP-NEN by p53-dependent repression of cell cycle and DNA repair-related genes and FOXM1 repression on at least the transcriptional and posttranslational level.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors

Briest¹,

Grass

Sedding

et al. 2017

Neuroendocrinology

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Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo.Methods: By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. Results: The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin-3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. Conclusion: In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors

Briest¹,

Grass

Sedding

et al. 2017

Neuroendocrinology

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“…Reactivation of the p53 pathway by MDM2 inhibition has been suggested as a promising therapeutic strategy in cancers retaining wild-type TP53 and several MDM2 antagonists are currently in clinical trials [104–107]. MDM2 antagonist nutlin-3 and its orally bioavailable analogues RG7388 and RG7112 disrupted interaction between p53 and MDM2 leading to stabilization of p53 [108, 109].…”

Section: Targeting Of Wip1 Phosphatase In Cancer Therapymentioning

confidence: 99%

WIP1 phosphatase as pharmacological target in cancer therapy

2017

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DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.

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“…This clearly indicates that dual inhibition of the p53 interaction with MDM2 and MDMX may substantially improve the outcome of this p53 activation strategy due to the full p53 activation [2]. In spite of this, to date, just few small molecule dual inhibitors of the p53-MDMs interaction have been identified, namely a pyrrolopyrimidine [4], an indolylhydantoin (RO-5963; [3]) and a cis-imidazoline derivative (H109; [5]). …”

Section: Introductionmentioning

confidence: 99%

A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins

Soares

Raimundo

Pereira

et al. 2015

Pharmacological Research

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Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) proteins, MDM2 and MDMX, is a common event in human tumors expressing wild-type p53. In these tumors, the simultaneous inhibition of these interactions with MDMs, for a full p53 reactivation, represents a promising anticancer strategy. Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay. With human colon adenocarcinoma HCT116 cell lines expressing wild-type p53 (HCT116 p53(+/+)) and its p53-null isogenic derivative (HCT116 p53(-/-)), it was shown that OXAZ-1 induced a p53-dependent tumor growth-inhibitory effect. In fact, OXAZ-1 induced p53 stabilization, up-regulated p53 transcription targets, such as MDM2, MDMX, p21, Puma and Bax, and led to PARP cleavage, in p53(+/+), but not in p53(-/-), HCT116 cells. In addition, similar tumor cytotoxic effects were observed for OXAZ-1 against MDMX-overexpressing breast adenocarcinoma MCF-7 tumor cells, commonly described as highly resistant to MDM2-only inhibitors. In HCT116 p53(+/+) cells, the disruption of the p53 interaction with MDMs by OXAZ-1 was further confirmed by co-immunoprecipitation. It was also shown that OXAZ-1 potently triggered a p53-dependent mitochondria-mediated apoptosis, characterized by reactive oxygen species generation, mitochondrial membrane potential dissipation, Bax translocation to mitochondria, and cytochrome c release, and exhibited a p53-dependent synergistic effect with conventional chemotherapeutic drugs. Collectively, in this work, a novel selective activator of the p53 pathway is reported with promising antitumor properties to be explored either alone or combined with conventional chemotherapeutic drugs. Moreover, OXAZ-1 may represent a promising starting scaffold to search for new dual inhibitors of the p53-MDMs interaction.

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Efficient Reactivation of p53 in Cancer Cells by a Dual MdmX/Mdm2 Inhibitor

Cited by 20 publications

References 33 publications

Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors

Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors

WIP1 phosphatase as pharmacological target in cancer therapy

A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins

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