Abstract 3348: Inhibition of MDMX by XI-011 induces p53-mediated apoptosis in head and neck cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Overexpression of MDM2 or MDMX inactivates the tumor-suppressive function of p53. Restoration of p53 function counteracting these p53 repressors can lead to in vivo tumor regression. Therefore, we evaluated whether the restoration of p53 function by a small-molecule p53 activator XI-011, a pseudouria derivative NSC146109, induce apoptosis in head-and-neck cancer (HNC). The effects of XI-011 treatment in four HNC cell lines were tested, individually or in combination with nutlin-3a, an inhibitor of MDM2-p53 interactions, and its growth suppression, cell-cycle arrest, and apoptosis were assessed. XI-011 induced accumulation and reactivation of p53 in a wild-type TP53-bearing HNC cell line. XI-011 showed maximal growth suppression in tumor cells with overexpression of MDMX and MDMX-dependent p53 degradation. With down-regulation of MDMX mRNA and protein levels, XI-011 upregulated expression of p21 and proapoptotic genes and promoted apoptosis in a dose-dependent manner. Notably, the apoptotic response was blocked by inhibition of p53 or MDMX gene expression, demonstrating the p53 and MDMX dependence of XI-011 effects. XI-011 decreased the viability of HNC cells expression low levels of MDMX in a less-efficient manner. Interestingly, in combination therapy, XI-011 synergistically acted with nutlin-3a to inhibit growth of HNC cells. Our data suggest that the MDMX inhibition and p53 functional restoration by XI-011 effectively induced cytotoxicity and apoptosis in cancer cells, an action that may offer a promising strategy for treating HNC. Citation Format: In Sun Ryu, Chang Hwan Ryu, Hyun Bae Park, Eunhye Kim, Jong-Lyel Roh. Inhibition of MDMX by XI-011 induces p53-mediated apoptosis in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3348. doi:10.1158/1538-7445.AM2013-3348