Abstract 2155: Small molecule NSC59984 suppresses cancer cell growth under hypoxia

Abstract

Abstract Hypoxia is one of the main features of solid tumors, contributes to drug resistance and is associated with poor prognosis. We have reported that a small-molecule NSC59984 restores p53 signaling and degrades mutant p53 protein in cancer cells. We find that NSC59984-mediated p53 signaling restoration and mutant p53 degradation is significantly blocked by NAC, an inhibitor of reactive oxygen species (ROS), while, further enhanced by BSO, a chemical compound increasing ROS in cells. These results suggest that ROS is a factor required for the effect of NSC59984 on cancer cells. Cellular ROS is produced by hypoxia in solid tumors. We investigated the effect of NSC59984 on p53 pathway and cell death in p53 mutant colorectal cancer (CRC) cells cultured under hypoxia. NSC59984 increases p53 signaling in p53 mutant cancer cells under hypoxia, as it does under normoxia. The effect of NSC59984 under hypoxia is blocked by NAC. Moreover, NSC59984 decreases cancer cell viability in a dose-dependent manner under hypoxia similar to normoxia. Our results suggest that NSC59984 inhibits cancer cell growth under hypoxia. Hypoxia has been known to increase cancer stem cells in tumors, which is one of the reasons causing drug resistance. We then evaluate the effect of NSC59984 on the stem cell growth. NSC59984 significantly reduces colonosphere formation of SW480, DLD-1 and HT29 cells. CRC stem cell markers such as CD44 and ALDH are decreased in colonospheres upon NSC59984 treatment, suggesting that NSC59984 inhibits stem cell self-renewal or/and growth. Our results provide the rationale for administration of NSC59984 in solid tumors with or without hypoxia and in combination treatment with ROS activators. Citation Format: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry. Small molecule NSC59984 suppresses cancer cell growth under hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2155. doi:10.1158/1538-7445.AM2017-2155