Abstract B288: 17AAG enhances cisplatin-induced cytotoxicity to induce p53-mediated apoptosis in head and neck cancer.

Purpose: Tumor suppressor p53 is often inactivated in head and neck cancer (HNC) because of TP53 mutations or the overexpression of MDM2 or MDMX. Restroation of p53 function through counteracting these p53 repressors is considered a promising strategy for cancer treatment. Therefore, we examined the role of a heat shock protein 90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), in inducing apoptosis in HNC by restoring p53 function. Experimental Design: In five HNC cell lines, we tested the effects of 17AAG treatment, either individually or in combination with 17AAG or cisplatin and assessed growth suppression, cell cycle arrest, and apoptosis assay. Results: 17AAG activated and stabilized p53 in an HNC cell line bearing wild-type TP53 by disrupting the p53-MDMX interaction. 17AAG upregulated expression of p21 and proapoptotic genes and promoted apoptosis, in a dose-dependent manner. 17AAG exerted the highest growth suppression in tumor cells with MDMX overexpression. The apoptotic response was blocked by inhibition of p53 or MDMX expression, demonstrating that the effects of 17AAG depend on p53 and MDMX. In combination treatments, 17AAG acted synergistically with Nutlin-3a to inhibit growth of HNC cells. 17AAG also synergized the antitumor effect of cisplatin by inducing p53-mediated apoptosis. Conclusion: 17AAG effectively induced p53-mediated apoptosis in HNC cells by MDMX inhibition, suggesting a promising strategy for treating HNC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B288. Citation Format: Minsu Kwon, Eun Hye Kim, Hyun Bae Park, Sang Yoon Kim, Jong-Lyel Roh. 17AAG enhances cisplatin-induced cytotoxicity to induce p53-mediated apoptosis in head and neck cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B288.