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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)517-532
Number of pages16
JournalOncoscience
Volume2
Issue number5
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Adenocarcinoma
Reactive Oxygen Species
Cell Death
Iron
Apoptosis
Cell Line
Antimalarials
artesunate
Lipid Peroxidation
Cell Survival
Homeostasis
Necrosis
Antioxidants
Epithelial Cells
Cell Proliferation
Messenger RNA
Neoplasms

Keywords

  • Artesunate
  • Cell death
  • Ferroptosis
  • KRas
  • Necroptosis
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. / Eling, Nils; Reuter, Lukas; Hazin, John; Hamacher-Brady, Anne; Brady, Nathan Ryan.

In: Oncoscience, Vol. 2, No. 5, 2015, p. 517-532.

Research output: Contribution to journalArticle

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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.",
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