| http://purl.uniprot.org/citations/20680659 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/20680659 | http://www.w3.org/2000/01/rdf-schema#comment | "Nutlin-3, a small-molecule MDM2 inhibitor, restores p53 function and is, thus, an appealing candidate for the treatment of cancers retaining wild-type p53. However, nutlin-3 applied as single agent may be insufficient for cancer therapy. Therefore, we explored whether the anticancer activity of nutlin-3 could be enhanced by combination with histone deacetylase inhibitors (HDACi), i.e. vorinostat, sodium butyrate, MS-275 and apicidin. We found that nutlin-3 and HDACi cooperated to induce cell death in the p53 wild-type cell lines A549 and A2780, but not in the p53 null cell line PC-3, as assessed by Alamar Blue assay and flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization. Combination index analysis showed that the effect was synergistic. For comparison, we tested nutlin-3 in combination with paclitaxel, revealing that nutlin-3 antagonized the cytotoxic activity of paclitaxel. To shed light on the underlying mechanism of the synergistic action of nutlin-3 and HDACi, we determined the acetylation status of p53 by immunoblotting and the mRNA levels of MDM2 and MDM4 by real-time RT-PCR. We observed vorinostat to induce p53 hyperacetylation, to reduce the constitutive gene expression of MDM2 and MDM4, and to counteract the nutlin-3-induced upregulation of MDM2 gene expression. In conclusion, our study shows that HDACi amplify the antitumor activity of nutlin-3-possibly by inducing p53 hyperacetylation and/or MDM2 and/or MDM4 downregulation-suggesting that treatment with a combination of nutlin-3 and HDACi may be an effective strategy for treating tumors with wild-type p53."xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.org/dc/terms/identifier | "doi:10.1007/s10637-010-9510-7"xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/author | "Sonnemann J."xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/author | "Beck J.F."xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/author | "Palani C.D."xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/date | "2012"xsd:gYear |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/name | "Invest New Drugs"xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/pages | "25-36"xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/title | "Histone deacetylase inhibitors enhance the anticancer activity of nutlin-3 and induce p53 hyperacetylation and downregulation of MDM2 and MDM4 gene expression."xsd:string |
| http://purl.uniprot.org/citations/20680659 | http://purl.uniprot.org/core/volume | "30"xsd:string |
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