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

Nils Eling, Lukas Reuter, John Hazin, Anne Hamacher-Brady, Nathan R. 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 - Jan 1 2015

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Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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