Analysis of the MDM2 antagonist nutlin-3 in human prostate cancer cells

BACKGROUND Small molecule MDM2 antagonists including nutlin‐3 have been shown to be effective against a range of cancer cell types and nutlin‐3 can inhibit growth of LNCaP xenografts. We compared the efficacy of nutlin‐3 in three prostate cancer cell types and provide an insight into the mechanism of nutlin‐3. METHODS Nutlin‐3 efficacy was measured using proliferation assays, cell cycle analysis, apoptosis assays, quantitative RT‐PCR, and immunoblotting. Chromatin immunoprecipitation (ChIP) assays were also performed. RESULTS Nutlin‐3 can specifically inhibit proliferation of LNCaP cells through cell cycle arrest and apoptosis. This coincides with increased levels of the p53‐responsive transcripts p21, PUMA, gadd45, and Mdm2 and recruitment of p53 to chromatin. Nutlin‐3 also reduces androgen receptor levels, resulting in altered receptor recruitment to chromatin. CONCLUSION Our study demonstrates that small molecule MDM2 antagonists might be useful in the treatment of human prostate cancers that retain functional p53 and androgen receptor signaling. Prostate 67: 900–906, 2007. © 2007 Wiley‐Liss, Inc.