title: Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells.
abstract: 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.
authors.affiliation: Lysosomal Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Systems Biology of Cell Death Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany ; BioQuant, University of Heidelberg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Eling
authors.affiliation: Lysosomal Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Systems Biology of Cell Death Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany ; BioQuant, University of Heidelberg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Reuter
authors.affiliation: Systems Biology of Cell Death Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany ; BioQuant, University of Heidelberg, Germany.
authors.forename: John
authors.initials: J
authors.lastname: Hazin
authors.affiliation: Lysosomal Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; BioQuant, University of Heidelberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Hamacher-Brady
authors.affiliation: Systems Biology of Cell Death Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany ; BioQuant, University of Heidelberg, Germany.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Brady
keywords: KRas; artesunate; cell death; ferroptosis; necroptosis; pancreatic cancer