The p53-reactivating small-molecule RITA enhances cisplatin-induced cytotoxicity and apoptosis in head and neck cancer

Jong Lyel Roh, Jung Ho Ko, Soo Jin Moon, Chang Hwan Ryu, Jun Young Choi, Wayne M. Koch

Research output: Contribution to journalArticlepeer-review

Abstract

We evaluated whether the restoration of p53 function by the p53-reactivating small molecule RITA (reactivation of p53 and induction of tumor cell apoptosis enhances cisplatin-induced cytotoxicity and apoptosis in head-and-neck cancer (HNC). RITA induced prominent accumulation and reactivation of p53 in a wild-type TP53-bearing HNC cell line. RITA showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. RITA promoted apoptosis in association with upregulation of p21, BAX, and cleaved caspase-3; notably, the apoptotic response was blocked by pifithrin-α, demonstrating its p53 dependence. With increasing concentrations, RITA strongly induced apoptosis rather than G2-phase arrest. In combination therapy, RITA enhanced cisplatin-induced growth inhibition and apoptosis of HNC cells invitro and in vivo. Our data suggest that the restoration of p53 tumor-suppressive function by RITA enhances the cytotoxicity and apoptosis of cisplatin, an action that may offer an attractive strategy for treating HNC.

Original languageEnglish (US)
Pages (from-to)35-41
Number of pages7
JournalCancer Letters
Volume325
Issue number1
DOIs
StatePublished - Dec 1 2012

Keywords

  • Apoptosis
  • Head and neck cancer
  • P53
  • RITA
  • Reactivation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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