Artemisinin-Type Drugs in Tumor Cell Death: Mechanisms, Combination Treatment with Biologics and Nanoparticle Delivery

Abstract

Artemisinin, the most famous anti-malaria drug initially extracted from Artemisia annua L., also exhibits anti-tumor properties in vivo and in vitro. To improve its solubility and bioavailability, multiple derivatives have been synthesized. However, to reveal the anti-tumor mechanism and improve the efficacy of these artemisinin-type drugs, studies have been conducted in recent years. In this review, we first provide an overview of the effect of artemisinin-type drugs on the regulated cell death pathways, which may uncover novel therapeutic approaches. Then, to overcome the shortcomings of artemisinin-type drugs, we summarize the recent advances in two different therapeutic approaches, namely the combination therapy with biologics influencing regulated cell death, and the use of nanocarriers as drug delivery systems. For the former approach, we discuss the superiority of combination treatments compared to monotherapy in tumor cells based on their effects on regulated cell death. For the latter approach, we give a systematic overview of nanocarrier design principles used to deliver artemisinin-type drugs, including inorganic-based nanoparticles, liposomes, micelles, polymer-based nanoparticles, carbon-based nanoparticles, nanostructured lipid carriers and niosomes. Both approaches have yielded promising findings in vitro and in vivo, providing a strong scientific basis for further study and upcoming clinical trials.

Keywords: artemisinin; combination treatment; nanoparticle delivery; regulated cell death.

Figure 1

Artemisinin and four derivatives in clinical application.

Figure 2

Artemisinin-type drugs influence several RCD pathways. The red arrows represent the upregulation or downregulation of certain key players on protein level. (I) ART-type drugs produce ROS resulting in increased expression of death receptors, and cleavage of caspase-3 and caspase-8, and decreased c-FLIP expression, leading to stimulation of the extrinsic apoptosis pathway. Meanwhile, ROS itself also triggers the intrinsic apoptosis pathway by upregulating the expression of tBID, BAX/BAK, inducing the release of Cytochrome C to activate caspase-9. (II) ROS accumulation from ART-type drugs results in lipid peroxidation to induce ferroptosis. Besides, the disruption of the oxidative homeostasis maintaining system by ART-type drugs leads to downregulation of GPX4 expression. (III) The oxidative stress from ART-type drugs initiates the formation of the phagophore via activating the AMPK pathway and assembling the VPS34 complex, resulting in autophagy. ART-type drugs also increase MLKL pore formation to induce necroptosis (IV), or GSDME-NT pore formation to induce pyroptosis (V).