Abstract 961: Selectively kill cisplatin resistant lung cancer cells by exploiting ROS and metabolic differences.

Abstract

Abstract Cisplatin resistance remains a clinical challenge for the treatment of lung cancer. We have previously shown that all cisplatin resistant (CR) cells tested have high ROS and low thioredoxin-1 (TRX1) protein. These biochemical changes lead to metabolic re-programming and hence these CR cells depend on fatty acid (FA) metabolism. To further confirm these finding, here we show a correlation between the levels of cisplatin resistance and ROS production, intracellular TRX1 levels and metabolic changes in tumor cells. We have established multiple CR clones with different levels of CR from small cell and non small cell lung cancer H69 and H460 (purchased from ATCC) and from cell lines derived from our lung cancer patients (SCLC1 and NSCLCS). These clones have different levels of cisplatin resistance ranging from 2, 5, to 10 fold. The stepwise increases in cisplatin resistance are correlated with a progressive increase in ROS production while intracellular TRX1 levels are gradually decreasing. Furthermore, CR cells which are highly resistant to cisplatin (2-3fold or more) with high ROS levels are hypersensitive to ROS inducing agent, elesclomol. Importantly, when ROS production increased by 5% or more, lung cancer cells become more sensitive to an agent that interferes with the FA synthesis pathway such as TOFA (an acetyl-coA carboxylase inhibitor) but resistant to glycolytic inhibitors. Thus, our data suggest that CR cells were no longer dependant on glycolysis, but instead are reliant on oxidative metabolism (OXMET). Since CR cells are sensitive to elesclomol, we have investigated whether combination of TOFA and elesclomol can increase cell death in CR cells. Our data showed that elesclomol alone at 5nM results in 35-40% cell death in 72hr. Interestingly, combination treatment with a non-toxic dose of TOFA (0.1μg/ml) resulted in significant increase in cell death to 70%; (p<0.05). At a higher dose of elesclomol (10nM) which yield 50% cell death, combination with TOFA (0.1ug/ml) results in 95% cell death (p<0.05). Our findings strongly suggest that the levels of cisplatin resistance correlate with the levels of ROS production but inversely correlate with intracellular TRX1. When ROS production increases, these CR cells also become less addicted to glucose, but use FA as their energy source. Thus, by targeting ROS (elesclomol) and OXMET (TOFA), one can successfully kill CR cells without significant effect to normal cells (LL24, a lung fibroblast as control). Overall, these findings could have future implications for drug development to selectively target and eliminate CR tumors with a high ROS and low TRX1profile. Supported by James and Esther King Florida Biomedical Research. Citation Format: Medhi Wangpaichitr, George Theodoropoulos, Chunjing Wu, Nivit Poochareon, Ying Ying Li, Min You, Macus T. Kuo, Lynn G. Feun, Niramol Savaraj. Selectively kill cisplatin resistant lung cancer cells by exploiting ROS and metabolic differences. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 961. doi:10.1158/1538-7445.AM2013-961