DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin
Abstract
Dihydroartemisinin (DHA) has been shown to be capable of inhibiting cancer growth, whereas it remains largely elusive that the underlying molecular mechanism of DHA induced acute myeloid leukemia (AML) cell death. In the present study, we examined the effects of DHA on the proliferation and ferroptosis of AML cells as well as to elucidate the underlying molecular mechanisms. We found that DHA strongly inhibited the viability of AML cell lines and arrest cell cycle at G0/G1 phase. Further studies found that DHA effectively induced AML cells ferroptosis, which was iron-dependent and accompanied by mitochondrial dysfunction. Mechanistically, DHA induced autophagy by regulating the activity of AMPK/mTOR/p70S6k signaling pathway, which accelerated the degradation of ferritin, increased the labile iron pool, promoted the accumulation of cellular ROS and eventually led to ferroptotic cell death. Over expression of ISCU (Iron-sulfur cluster assembly enzyme, a mitochondrial protein) significantly attenuated DHA induced ferroptosis by regulating iron metabolism, rescuing the mitochondrial function and increasing the level of GSH. Meanwhile, FTH reconstituted AML cells also exhibited the reduced lipid peroxides content and restored the DHA-induced ferroptosis. In summary, these results provide experimental evidences on the detailed mechanism of DHA-induced ferroptosis and reveal that DHA might represent a promising therapeutic agent to preferentially target AML cells.
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Eprenetapopt is the first compound to reach a phase 3 clinical trial where triggering ferroptosis is central to its anticancer efficacy.
“eprenetapopt is the first compound to reach a phase 3 clinical trial where triggering ferroptosis is central to its anticancer efficacy.”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [38]
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“While other clinical compounds including sorafenib ( 37 ), sulfasala-zine ( 21 ), artemisinin ( 38 ), and statins, as well as conventional chemotherapy, immune checkpoint inhibitors, and radiotherapy ( 39 ), have demonstrated capacity to induce or enhance sensitivity to ferroptosis, eprenetapopt is…”
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- Authors
- Du, J., Wang, T., Li, Y., Zhou, Y., Wang, X., Yu, X., Ren, X., An, Y., Wu, Y., Sun, W., Fan, W., Zhu, Q., Wang, Y., & Tong, X.
- Affiliations
- Zhejiang Provincial People's Hospital (CN)
- Zhejiang Chinese Medical University (CN)
- Corresponding author
- Wang, Ying
- Tong, Xiangmin
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 131
- Pages
- 356-369
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2905446980
- Cited by
- 487
- References
- 8
- Citations by year
- 2026: 31 · 2025: 56 · 2024: 92 · 2023: 98 · 2022: 84 · 2021: 76 · 2020: 31 · 2019: 17
- FWCI
- 23.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science and Technology Major Project for New Drug (2017ZX301033)
- National Natural Science Foundation of China (81570198)
- Co Construction of Provincial and Department Project (WKJ-ZJ-1709)
- Key Projects of Zhejiang Provincial Administration of Traditional Chinese Medicine (2016ZZ007)
- Medical and Health Science and Technology Project of Zhejiang Province (2017KY209)
- Zhejiang Public Welfare Technology Application Research Project (LGF19H080006)
- Outstanding Youth Foundation of Zhejiang Provincial People's Hospital (ZRY2016B007, ZRY2016A003)
- Clinical and Scientific Research Project of Zhejiang Medical Association (2017ZYC-A14)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- dihydroartemisinin, acute myeloid leukemia, ferroptosis, autophagy, ferritin degradation, iron metabolism, IscU, mitochondrial dysfunction, reactive oxygen species, lipid peroxidation, G0/G1 cell cycle arrest, leukemia cell proliferation
- MeSH terms
- THP-1 Cells, Ferroptosis, Animals, Antimalarials, Antineoplastic Agents, Apoferritins, Autophagy, Cell Cycle, Humans, Iron-Sulfur Proteins, Mice, Nude, Mitochondria, Signal Transduction, Leukemia, Myeloid, Acute, Gene Expression Regulation, Leukemic, Reactive Oxygen Species, HL-60 Cells, Xenograft Model Antitumor Assays, Artemisinins, Ribosomal Protein S6 Kinases, 70-kDa, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Mice, Membrane Potential, Mitochondrial, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases, Proteolysis
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