Abstract 3950: Small molecule NSC59984 synergizes with ROS-generating agents to induce cell death via reduced GSH in cancer cells

Abstract

Abstract NSC59984 is a small molecule with a duel capability to induce mutant p53 degradation and restore p53 pathway signaling in cancer cells. NSC59984 requires reactive oxygen species (ROS) to induce mutant p53 degradation via ERK2. ROS regulates cell growth and death with tumor cells having higher ROS levels than normal cells. Increasing ROS level is a promising therapeutic strategy applied in cancer clinical trials. However, the toxicity of high ROS levels is a limitation that needs to be solved urgently. We investigated the synergy between NSC59984 and ROS in cancer cells. To increase ROS, cells were treated with BSO, an ROS-generating agent. Our data reveal that ROS sensitizes cells to NSC59984 treatment including enhanced-p53 restoration and mutant p53 degradation induced by NSC59984. Combination of NSC59984 and BSO shows a synergy to induce cell death in cancer cells with an antagonism observed in normal cells at the tested doses. Consistent with the in vitro experiments, our in vivo experiments show that the combination of NSC59984 and BSO significantly suppresses tumor growth. Immunohistochemical staining shows a decrease in Ki67 and an increase in cleaved caspase 3 in xenografted tumors following combination treatment, suggesting that the tumor suppression is due to the induction of cell death and the inhibition of cell growth. Furthermore, the combination of NSC59984 and BSO shows a significant reduction in glutathione (GSH) levels in cancer cells, suggesting that the synergy between NSC59984 and BSO is due to the inhibition of the antioxidant system in mutant p53-expressing cancer cells. Our data indicate that a high level of ROS can be considered as a biomarker for NSC59984 administration in cancer therapy and supports further evaluation of the combination of NSC59984 and ROS-generating agents. Citation Format: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry. Small molecule NSC59984 synergizes with ROS-generating agents to induce cell death via reduced GSH in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3950.