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Current Medicinal Chemistry

Author(s): Shunqin Zhu, Qin Yu, Chunsong Huo, Yuanpeng Li, Linshen He, Botian Ran, Ji Chen, Yonghao Li and Wanhong Liu*

DOI: 10.2174/0929867327666200121124404

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Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy

Page: [329 - 345] Pages: 17

  • * (Excluding Mailing and Handling)

Abstract

Background: Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular Reactive Oxygen Species (ROS) in cancer cells, which result in ferroptosis, a new form of cell death, depending on the ferritin concentration. Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy.

Methods: The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin-induced ferroptosis.

Results: Artemisinin derivatives, artemisinin-derived dimers, hybrids and artemisinin-transferrin conjugates, could significantly improve anticancer activity, and their IC50 values are lower than those of reference molecules such as doxorubicin and paclitaxel. The biological activities of linkers in dimers and hybrids are important in the drug design processes. ARTs induce ferroptosis mainly by triggering intracellular ROS production, promoting the lysosomal degradation of ferritin and regulating the System Xc-/Gpx4 axis. Interestingly, ARTs also stimulate the feedback inhibition pathway.

Conclusion: Artemisinin and its derivatives could be used in the future as cancer therapies with broader applications due to their induction of ferroptosis. Meanwhile, more attention should be paid to the development of novel artemisinin-related drugs based on the mechanism of artemisinininduced ferroptosis.

Keywords: Artemisinin derivatives, drug design, ferroptosis, cancer, system Xc-/Gpx4 axis, molecular mechanism.

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