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Eling N, Reuter L, Hazin J, et al. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience. 2015;2(5):517-32doi: 10.18632/oncoscience.160.
Eling, N., Reuter, L., Hazin, J., Hamacher-Brady, A., & Brady, N. R. (2015). Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience, 2(5), 517-32. https://doi.org/10.18632/oncoscience.160
Eling, Nils, et al. "Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells." Oncoscience vol. 2,5 (2015): 517-32. doi: https://doi.org/10.18632/oncoscience.160
Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience. 2015 May 02;2(5):517-32. doi: 10.18632/oncoscience.160. eCollection 2015. PMID: 26097885; PMCID: PMC4468338.
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Oncoscience. 2015 May 02;2(5):517-32. doi: 10.18632/oncoscience.160. eCollection 2015.

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

Oncoscience

Nils Eling, Lukas Reuter, John Hazin, Anne Hamacher-Brady, Nathan R Brady

Affiliations

  1. 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.
  2. 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.
  3. Lysosomal Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; BioQuant, University of Heidelberg, Germany.

PMID: 26097885 PMCID: PMC4468338 DOI: 10.18632/oncoscience.160

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.

Keywords: KRas; artesunate; cell death; ferroptosis; necroptosis; pancreatic cancer

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