Histone deacetylase inhibitors enhance the anticancer activity of nutlin-3 and induce p53 hyperacetylation and downregulation of MDM2 and MDM4 gene expression

Chithra D. Palani, James F. Beck, Jürgen Sonnemann

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)25-36
Number of pages12
JournalInvestigational New Drugs
Volume30
Issue number1
DOIs
StatePublished - Feb 2012
Externally publishedYes

Keywords

  • Histone deacetylase inhibitors
  • MDM2
  • MDM4
  • Nutlin-3
  • P53 acetylation
  • Paclitaxel

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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