Novel small molecules have been reported to restore the p53 tumor suppressor function inducing cell cycle arrest and apoptosis. The p53-targeting therapy may overcome the resistance to chemotherapeutic agents. This study evaluated whether small molecules induce p53-dependent apoptosis in head and neck squamous cell carcinoma (HNSCC) lines. PRIMA-1, CP-31398, RITA, and nutlin-3 were tested in 6 HNSCC cell lines with different p53 status and MDM2 expression levels. Cell growth, viability, cell cycle, and apoptosis after the treatment or combined treatment with common chemotherapeutic agents were assessed. The p53 reactivation was observed in mutant TP53-carrying cell lines by PRIMA-1 or CP-31398 treatment and in wild-type TP53-carrying cell lines by nutlin-3 treatment. The cell cycle arrest and apoptosis by the small molecules was associated with up-regulation of p21, Bax, and cleaved caspase-3. PRIMA-1 or CP-31398 induced also significant apoptosis in cell lines without p53 protein expression. Nutlin-3 or RITA showed maximal suppression in tumors with MDM2-induced tumor degradation. The small molecules enhanced the antitumor activity of the cell lines with a combination of cisplatin, 5-fluorouracil, paclitaxel, or erlotinib. The small molecules effectively restored p53 tumor suppressive function in HNSCC with mutant or wild-type p53. The p53 reactivating agents may be used for HNC with a combination of commonly-used chemotherapeutic agents.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4527.