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Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells

Oncogenic KRas reprograms pancreatic ductal adenocarcinoma (PDAC) cells to states which are highly resistant to apoptosis. Thus, a major preclinical goal is to identify effective strategies for killing PDAC cells. Artesunate (ART) is an anti-malarial that specifically induces programmed cell death i...

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Bibliographic Details
Main Authors: Eling, Nils (Author) , Hazin, John (Author) , Hamacher-Brady, Anne (Author) , Brady, Nathan (Author)
Format: Article (Journal)
Language:English
Published: May 2, 2015
In: Oncoscience
Year: 2015, Volume: 2, Issue: 5, Pages: 517-532
ISSN:2331-4737
DOI:10.18632/oncoscience.160
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.18632/oncoscience.160
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Author Notes:Nils Eling, Lukas Reuter, John Hazin, Anne Hamacher-Brady and Nathan R. Brady

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520 |a Oncogenic KRas reprograms pancreatic ductal adenocarcinoma (PDAC) cells to states which are highly resistant to apoptosis. Thus, a major preclinical goal is to identify effective strategies for killing PDAC cells. Artesunate (ART) is an anti-malarial that specifically induces programmed cell death in different cancer cell types, in a manner initiated by reactive oxygen species (ROS)-generation. In this study we demonstrate that ART specifically induced ROS- and lysosomal iron-dependent cell death in PDAC cell lines. Highest cytotoxicity was obtained in PDAC cell lines with constitutively-active KRas, and ART did not affect non-neoplastic human pancreatic ductal epithelial (HPDE) cells. We determined that ART did not induce apoptosis or necroptosis. Instead, ART induced ferroptosis, a recently described mode of ROS- and iron-dependent programmed necrosis which can be activated in Ras-transformed cells. Co-treatment with the ferroptosis inhibitor ferrostatin-1 blocked ART-induced lipid peroxidation and cell death, and increased long-term cell survival and proliferation. Importantly, analysis of PDAC patient mRNA expression indicates a dependency on antioxidant homeostasis and increased sensitivity to free intracellular iron, both of which correlate with Ras-driven sensitivity to ferroptosis. Overall, our findings suggest that ART activation of ferroptosis is an effective, novel pathway for killing PDAC cells. 
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