Cited by 530Ferroptosis and cancer prognosisCell death mechanisms and regulationPancreatic and Hepatic Oncology Research

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

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Eling, Nils, Reuter, Lukas, Hazin, John, Hamacher-Brady, Anne, Brady, Nathan R.·2015·Oncoscience

DOI 10.18632/oncoscience.160PMC PMC4468338

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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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Authors: Eling, N., Reuter, L., Hazin, J., Hamacher-Brady, A., & Brady, N. R.
Affiliations: German Cancer Research Center (DE)
Lysosomal Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
ORCID: Eling, Nils
Brady, Nathan R.
Venue: Oncoscience
Publisher: Impact Journals, LLC
Published: 2015-05-02
Volume: 2
Issue: 5
Pages: 517-532
ISSN: 2331-4737 (ISSN-L)
DOI: 10.18632/oncoscience.160
PMC: PMC4468338
OpenAlex: W2418439210
Cited by: 524
References: 59
Citations by year: 2026: 22 · 2025: 41 · 2024: 57 · 2023: 71 · 2022: 92 · 2021: 91 · 2020: 60 · 2019: 26 · 2018: 21 · 2017: 23 · 2016: 15 · 2015: 2
FWCI: 16.10
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: cc-by
Locations: Oncoscience (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Deutsches Krebsforschungszentrum
Bundesministerium für Bildung und Forschung
University of Toronto
Tianjin Medical University
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Keywords: artesunate, ferroptosis, pancreatic ductal adenocarcinoma, reactive oxygen species, lysosomal iron, lipid peroxidation, ferrostatin-1, antioxidant homeostasis, necroptosis, apoptosis resistance, anticancer drug repurposing

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

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