Abstract 2668: Radiosensitization of solid tumor cell lines by an MDM2 inhibitor

Abstract

Abstract The tumor suppressor p53 is a key molecule in the prevention of cancer. More than half of all human cancers have mutation or loss of the p53 gene. A significant percentage of the other half contain overexpression of Hdm2 which serves as a ubiquitin ligase (E3) to target p53 for degradation. While it has been established that an inhibitor of Hdm2 ubiquitin E3 ligase activity HLI373 (5-(3-dimethylaminopropylamino)-3,10-dimethyl-10H-pyrimido(4,5-b)quinoline-2,4-dione, NSC373989), selectively kills tumor cells harboring wild-type p53, we investigated the effect of the Hdm2 inhibitor HLI373, in the response to ionizing radiation in solid tumor lines expressing wild-type, mutant or null p53 in vitro and in vivo. We now report HLI373 enhances radiosensitivity in a panel of human tumor cell lines in p53 deficient and competent cell lines using clonogenic assay. HCT116 cells exposed to HLI373 (5-7.5 uM) for 16 hours before and maintained in the medium after irradiation had an increase in radiosensitivity. Cell cycle distribution of treated cells after 16 hours was measured using flow cytometry. In a comparison of wildtype and null cell lines, cell cycle arrest in G1 was only detected in cells with active p53 at 5uM of HLI373. In contrast, cells with a null or mutated p53 progressed to and arrested in G2. In addition, wild type p53 cells pretreated with 5 uM HLI373 and irradiated continued to be arrested in G1 and did not progress to a G2. However, cells without p53 treated with HLI373 and radiation increased in accumulation in G2. Treatment with higher dosages of HLI373 (>10uM) resulted in the accumulation of cells in G2 regardless of p53 status. These results indicate that HLI373 enhances tumor cell radiosensitivity in vitro and agents such as HLI373 may have potential for use in the clinics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2668. doi:10.1158/1538-7445.AM2011-2668