Abstract 4404: Novel approach to circumvent cisplatin resistant lung cancer by targeting metabolism
Authors: Medhi Wangpaichitr, Chunjing Wu, Ying Ying Li, Lynn G. Feun, Macus T. Kuo, Niramol Savaraj
Journal: Cancer Research (2017)

Abstract For the past three decades, there are no drugs which could reverse cisplatin resistance or selectively kill these resistant cells. We have discovered that cisplatin resistant (CR) lung cancer shares one common factor which is increase in reactive oxygen species (ROS). Decreased intracellular thioredoxin-1(TRX1) due to excessive secretion was found in vitro and in vivo, as well as in patients’ serum which could be a primary contributory factor to higher mitochondria-ROS levels. Furthermore, CR cells possess significantly increased number of mitochondria and consume higher rates of oxygen. Key glycolytic enzymes (HKII and LDHA) and lactate production were decreased in CR cells which suggests rewiring of tumor metabolic pathways. NAD+, crucial co-factor of all redox systems, is significantly reduced in all CR cells. Importantly, treatment with riluzole (the FDA approved drug that interferes with cystine/glutamate pump and results in reduced intracellular glutathione (GSH) levels) led to further decrease in NAD+ and LDHA, as well as heightened oxidative stress in CR cells. ROS levels were increased (2-3X) more in resistant cells after riluzole treatment while no significant change occurred in parental cells. The ID50 dosage of parental cells were 3-4 fold more than theirs CR cell counterparts and no cytotoxicity were found in normal lung fibroblast (n=8; p&amp;lt;0.05). Addition of 200 µM NAD+ re-stabilized LDHA, reduced ROS, and reversed riluzole induced cell death. To further determine whether LDHA correlates with ROS levels and sensitivity to riluzole, we inhibited LDHA expressions in parental cell lines S and H460 using siRNA. Lactate productions were decreased in knockdown cells and further attenuated upon riluzole treatment when compared with scrambled control. Higher basal levels of ROS were obtained from S+siLDHA and H460+siLDHA and further increased in ROS levels were observed when treated with riluzole. We then evaluated the viability of these cells under riluzole treatment. Both siLDHA clones were sensitive to riluzole particularly in S+siLDHA which showed 4 fold more sensitivity. Importantly, treatment of riluzole also led to further decrease in LDHA expressions at both protein and mRNA levels. Using riluzole in 2 mouse xenograft models (H460CR (KRAS mutant) and SC (wt)) resulted in completely disappeared in wild type mice and were significant reduced in KRAS mutant mice (n=5 per treatment group; p&amp;lt;0.002). Repurpose of riluzole should be considered for future treatment of CR lung cancer patients. Supported by Department of Veterans Affairs, CDA2 award (1K2BX001289) and Woman Cancer Association Fund. Citation Format: Medhi Wangpaichitr, Chunjing Wu, Ying Ying Li, Lynn G. Feun, Macus T. Kuo, Niramol Savaraj. Novel approach to circumvent cisplatin resistant lung cancer by targeting metabolism [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 4404. doi:10.1158/1538-7445.AM2017-4404