The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer

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.

Artesunate inhibits osteoclast differentiation by inducing ferroptosis and prevents iron overload‐induced bone loss

“…System xc‐/GSH/glutathione peroxidase 4 (GPX4) axis plays a pivotal role in preventing lipid peroxidation induced ferroptosis 17 . Artemisinin compounds can exert anticancer effects by inducing ferroptosis 18 . The underlying mechanisms are associated with the regulation of iron metabolism, ferritin autophagy, oxidative stress and endoplasmic reticulum stress 19–22 .…”

Identification of ATG7 as a Regulator of Proferroptosis and Oxidative Stress in Osteosarcoma

“…The intrinsic pathway was driven by blocking the intracellular antioxidant enzymes (like glutathione peroxidase, GPX4) [ 14 ]. However, the extrinsic pathway involved the inhibition of the cell membrane transporters like the cystine/glutamate transporter (also called the system Xc − ) or by the activation of the iron transporters like lactotransferrin and serotransferrin [ 29 ]. Furthermore, a few earlier studies also reported that many clinical drugs could initiate ferroptosis by inhibiting system Xc − or GPX4 [ 30 – 32 ], providing a new way of treating cancer for oncologists.…”

Identification of Novel Artemisinin Hybrids Induce Apoptosis and Ferroptosis in MCF-7 Cells

“…Ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death that is independent of caspase activation, is often accompanied by the accumulation of reactive oxygen species (ROS) and lipid peroxides, a decrease in reduced glutathione (GSH) levels and the downregulation of glutathione peroxidase 4 (GPX4) [ 27 , 28 ]. Recent studies indicate that the peroxide bridge of ART could destroy the redox balance in tumor cells, resulting in oxidative stress and ROS accumulation [ 10 , 29 ]. Thus, we speculated that ROS-induced ferroptosis also occurred.…”

“…Many drugs from natural products still have profound impacts on human beings [ 4 , 5 , 6 , 7 ]. Artemisinin (ART), an important naturally occurring endoperoxide-containing sesquiterpene lactone with excellent antimalarial activity, has also been proven to exhibit significant antitumor activity in recent research [ 8 , 9 , 10 ], and several successful structural modifications or hybrids of artemisinin have been reported [ 11 , 12 , 13 , 14 , 15 , 16 ] ( Figure 1 ).…”