Nutlin-3

Nutlin-3, a tetra-substituted imidazoline, is a potent and selective small-molecule antagonist of murine double minute 2 (MDM2), which occupies the binding site of p53 in MDM2 and consequently prevent MDM2 binding to p53 leading to the disruption of the autoregulator feedback loop and the fostering of the p53 tumor suppressor network. It also binds to murine double minute 4 (MDM4), which is another component of the p35 tumor surveillance pathway. Nutlin-3 is being investigated as an antitumor agent for its antiangiogenic activity in cells through inhibiting endothelial cell migration, inducing cell cycle arrest, and increasing apoptotic tendency in endothelial cells. 

Reference

Bernd R. Binder. A novel application for murine double minute 2 antagonists: the p53 tumor suppressor network also controls angiogenesis. Circ Res. 2007; 100: 13-14

Nutlin-3 reverses the epithelial-mesenchymal transition in gemcitabine-resistant hepatocellular carcinoma cells.[Pubmed:27430152]

Oncol Rep. 2016 Sep;36(3):1325-32.

Nutlin-3, a small molecule regulator of the tumor suppressor p53, targets the interaction between p53 and murine double minute 2 (MDM2) thereby promoting stabilization of p53 and subsequent p53dependent induction of apoptosis and cell cycle arrest. Recent studies have demonstrated that Nutlin3 plays a critical role in regulating tumor cell migration, invasion, metastasis, and drug resistance. Although these studies identified various biological functions of Nutlin3, our understanding of the exact molecular mechanisms of Nutlin3mediated antitumor activity remains incomplete. In this study, we elucidated a role of Nutlin3 in reversing the epithelialmesenchymal transition (EMT) in gemcitabine-resistant (GR) hepatocellular carcinoma (HCC) cells. We assessed the effect of Nutlin3 treatment on cell growth, migration, and invasion in both parental HCC cells and GR HCC cells. Moreover, we detected the expression of EMT markers in GR HCC cells treated with Nutlin3 by realtime RTPCR and western blot analysis, respectively. We found that Nutlin-3 inhibited cell migration and invasion in the GR HCC cells. Additionally, Nutlin3 treatment increased E-cadherin protein levels, but decreased the protein levels of vimentin, Snail and Slug in the GR HCC cells. Furthermore, we found that Smad2 was highly expressed in the GR HCC cells compared with their parental HCC cells, and Nutlin-3 treatment downregulated Smad2 expression in the GR HCC cells. Depletion of Smad2 retarded cell migration and regulated the expression of EMT markers in GR HCC cells similarly to Nutlin3 treatment. Our findings highlight an important role of Nutlin3 in reversing EMT in GR cells through regulation of Smad2 expression, suggesting that Nutlin-3 could be a potential agent for the treatment of HCC patients with gemcitabine resistance.

Nutlin-3 inhibits androgen receptor-driven c-FLIP expression, resulting in apoptosis of prostate cancer cells.[Pubmed:27729622]

Oncotarget. 2016 Nov 15;7(46):74724-74733.

Inhibition of androgen receptor (AR) signalling represents the conventional medical management of prostate cancer. Ultimately this treatment fails because tumors develop an incurable, castrate resistant phenotype, resulting in an unmet need for new treatments in prostate cancer. The AR remains a viable therapeutic target in castrate resistant disease, such that novel ways of downregulating AR activities are attractive as potential treatments. Here we describe a mechanism by which the AR can be downregulated by the MDM2 antagonist Nutlin-3, resulting in loss of pro-survival c-FLIP gene expression and apoptosis. We additionally show that loss of c-FLIP sensitises prostate cancer cells to Nutlin-3. Finally, we demonstrate that the unrelated MDM2 antagonist Mi-63 also impinges upon AR signalling, supporting the concept of future treatment of prostate cancer with MDM2 antagonists.

Nutlin-3, an Antagonist of MDM2, Enhances the Radiosensitivity of Esophageal Squamous Cancer with Wild-Type p53.[Pubmed:28341911]

Pathol Oncol Res. 2018 Jan;24(1):75-81.

Murine double minute 2 (MDM2) negatively regulates the activity of the p53 protein and plays a vital role in cell cycle arrest, apoptosis, and senescence mediated by p53. Nutlin-3, an antagonist of MDM2, is frequently used in anti-cancer studies. In many human tumors, Nutlin-3 stabilizes p53 status and enhances p53 expression in cells with wild-type p53. However, the effect of Nutlin-3 combined with radiotherapy on esophageal squamous cancer (ESCC) has not been reported. In this study, we examined whether Nutlin-3 increases the radiosensitivity of ESCC in vitro and in vivo.We chose two cell lines, ECA-109 (wild-type p53) and TE-13 (p53 mutated), for the following experiments. Cell proliferation and clonogenic survival experiments showed that Nutlin-3 inhibits the cell growth and colony formation of ECA-109 cells in a dose-dependent manner. Flow cytometry analysis showed that the apoptosis rate of ECA-109 cells co-treated with Nutlin-3 and irradiation(IR) was significantly increased compared with cells treated with irradiation or Nutlin-3 alone. Western blotting detected the expression of apoptosis-associated proteins in ECA-109 cells in response to Nutlin-3 and irradiation. These effects were not evident in TE-13 cells. Xenograft mouse models indicated that Nutlin-3 suppresses tumor growth and promotes radiosensitivity in the ESCC cell line ECA-109 in vivo. We have demonstrated that co-treatment of Nutlin-3 with irradiation can significantly inhibit the growth and improve the radiosensitivity of ESCC cells with wild-type p53. The study suggests that Nutlin-3 may be a potent therapeutic agent in conjunction with radiotherapy in ESCC.

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.[Pubmed:27223080]

Oncotarget. 2016 Jun 28;7(26):40115-40134.

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.

Nutlin-3 is a potent and selective Mdm2 (RING finger-dependent ubiquitin protein ligase for itself and p53) antagonist with IC50 of 90 nM in a cell-free assay; stabilizes p73 in p53-deficient cells.

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