Abstract
Artemisinin (ART) is a bioactive molecule derived from the Chinese medicinal plant Artemisia annua (Asteraceae). ART and artemisinin derivatives (ARTs) have been effectively used for antimalaria treatment. The structure of ART is composed of a sesquiterpene lactone, including a peroxide internal bridge that is essential for its activity. In addition to their well-known antimalarial effects, ARTs have been shown recently to resist a wide range of tumors. The antineoplastic mechanisms of ART mainly include cell cycle inhibition, inhibition of tumor angiogenesis, DNA damage, and ferroptosis. In particular, ferroptosis is a novel nonapoptotic type of programmed cell death. However, the antitumor mechanisms of ARTs by regulating ferroptosis remain unclear. Through this review, we focus on the potential antitumor function of ARTs by acting on ferroptosis, including the regulation of iron metabolism, generation of reactive oxygen species (ROS), and activation of endoplasmic reticulum stress (ERS). This article systematically reviews the recent progress in ferroptosis research and provides a basis for ARTs as an anticancer drug in clinical practice.
Highlights
Ferroptosis is a novel form of cell death characterized by lipid peroxidation and reactive oxygen species (ROS) production due to iron accumulation [19]
Under sustained oxidative stress, tumor cells become well-adapted to such stress through a set of mechanisms, and they often have defects in cell death executioner mechanisms, which is one of the main causes of therapy resistance
Ferroptosis compared to apoptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer
Summary
Ferroptosis is a new type of cell death defined by Dixon et al in 2012 [18] and is characterized by the accumulation of lipid peroxidation and iron, the effects of which can be inhibited by iron chelators [19]. The anti-inflammatory drug sulfasalazine [32] and the tumor-targeting drug sorafenib [33] can inhibit the effect of system Xc-, thereby reducing intracellular Cys uptake and decreasing GSH synthesis, resulting in cell death. ART can cause ferroptosis in Ras mutant pancreatic cancer cells [37] It can induce ferroptosis in leukemia cells in a non-Ras-dependent manner [38]. An accumulating body of research suggests that ART may induce ferroptosis in cancer cells by regulating the above molecules. ARTs are a class of ferroptosis inducers and have been shown to inhibit the growth of various malignancies such as head and neck cancer [46], liver cancer [45], glioma [47], and bladder cancer [48]; the molecular mechanisms of how it affects ferroptosis remain unclear
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