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Nutlin-3, a compound identified as a selective and potent hdm2-p53 inhibitor, is a small molecule that binds hdm2 and renders it inaccessible to p53 thus preventing p53 from degradation. Moreover, it has been demonstrated to induce the arrest of tumour proliferation in vitro and in vivo employing different tumour model systems. Glioblastoma multiforme, the most aggressive astrocytic form of gliomas, is known to show aberrations in the p53 pathway in a high percentage of cases and inactivating p53 mutations and amplifications of hdm2 were found to be mutually exclusive. A therapeutic strategy targeting glioblastoma cells with amplified or overexpressed hdm2 to undergo apoptosis or stop proliferation might be feasible.

Employing a panel of glioblastoma cell lines differing in their p53 status we show that in p53 wt cell lines (expressing hdm2 to various levels) the p53 pathway is reactivated by nutlin-3 treatment as demonstrated by p53 protein induction and transcriptional upregulation of different p53 target genes such as p21 and mdm2. The phenotypic result is that p53 wt cells are inhibited in their proliferation to a greater extent than p53 mut cell lines. In a p53 wt background, this inhibition of proliferation is due to cell cycle arrest in G2/M phase and not to caspase-driven apoptosis since caspase 3 was not activated. Taken together, our data suggest that in glioblastoma cells another form of cellular death might play a role in the response to nutlin-3.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA