Ferroptosis, a morphologically and biochemically distinct cell death pathway, is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells. This cell death was blocked by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The objective of the present study was to determine whether lysosome disruptors and tyrosine kinase inhibitors, in combination, induced synergic cell death via the ferroptotic pathway in additional types of cancer. U87 (glioblastoma) and A549 (lung adenocarcinoma) cells were treated with various lysosome disruptors (siramesine or desipramine) in combination with tyrosine kinase inhibitors (lapatinib or sorafenib), and the amount of cell death was measured by trypan blue exclusion. We found that these combinations synergistically induced cell death in U87 and A549 cells. To determine whether ferroptosis was the mechanism of cell death, cells were pretreated with either Fer-1 or DFO (inhibitors of ferroptosis), or with exogenous iron chloride (an inducer of ferroptosis) before treatment with the combination of siramesine and lapatinib. Pretreatment with Fer-1 or DFO decreased cell death by approximately 35%. Pretreatment with iron chloride increased the effect of the drug combination by approximately 45%. Prussian Blue staining demonstrated that there was an increase in intracellular iron accumulation following treatment with the combination of siramesine and lapatinib. Collectively, these data show that in U87 and A549 cells, the combination of lysosome disruptors and tyrosine kinase inhibitors, specifically siramesine and lapatinib, induces ferroptotic cell death. Therefore, inducing ferroptosis in tumor cells is a potential strategy for therapy in these cancers with limited treatment options.

Citation Format: Anna R. Blankstein, Shumei Ma, Spencer B. Gibson. Siramesine and lapatinib induce ferroptosis in glioblastoma and lung adenocarcinoma cells [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 4293. doi:10.1158/1538-7445.AM2017-4293