Abstract 3729: Targeting breast cancer stem cells via oxidative stress with inhibitors of hydroperoxide metabolism and decyl-triphenylphosphonium.

Abstract

Cancer stem cells (CSCs) exhibit lower intracellular reactive oxygen species (ROS) levels than non-CSCs, which may be due to the increased expression of free radical scavenging systems. Exogenous agents may be useful to increase ROS and selectively kill CSCs by oxidative stress. Here we tested a combination approach to increase ROS as an effective strategy to eradicate breast CSCs and metastases. Buthionine sulfoximine (BSO) and auranofin (AU) were used to deplete glutathione (GSH) and inhibit thioredoxin reductase (TR), respectively, while mitochondrial-targeted decyltriphenylphosphonium (dTPP) was used to elevate ROS levels. In vitro clonogenicity assays using SUM159 cells showed that treatment with dTPP alone resulted in <30% survival, while AU+BSO, BSO+dTPP and AU+BSO+dTPP all resulted in <1% survival. These effects were reversible with N-acetylcysteine pre-treatment. The Aldefluor+ (CSC) population was also measured following drug treatment in vitro. dTPP or AU treatment alone resulted in <50% of CSCs remaining, while BSO+AU or BSO+dTPP resulted in <25% of CSCs remaining, and treatment with all three compounds resulted in <1% of CSCs remaining. In a preclinical model of breast cancer metastasis, long-term adjuvant treatment with each individual compound significantly reduced the amount of metastases and increased survival, with dTPP treatment alone resulting in 100% survival rate. Interestingly, the combination of all three compounds resulted in increased metastases compared to the single agents. This may potentially be a stress-induced effect resulting from drug toxicity. In conclusion, the approach of increasing ROS in breast cancer cells may be an effective way to target CSCs and useful for adjuvant therapy to reduce metastases in patients.

Citation Format: Sarah J. Conley, Trenton Baker, Rebecca Theisen, Elizabeth Gheordunescu, Yueming Zhu, Nukhet Aykin-Burns, Melissa Fath, Douglas Spitz, Max Wicha. Targeting breast cancer stem cells via oxidative stress with inhibitors of hydroperoxide metabolism and decyl-triphenylphosphonium. [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 3729. doi:10.1158/1538-7445.AM2013-3729