Evaluation of the Combined Effect of Artemisinin and Ferroptosis Inducer RSL3 against Toxoplasma gondii

Abstract

Toxoplasma gondii is a widespread intracellular pathogen that infects humans and a variety of animals. Dihydroartemisinin (DHA), an effective anti-malarial drug, has potential anti-T. gondii activity that induces ferroptosis in tumor cells, but the mechanism by which it kills T. gondii is not fully understood. In this study, the mechanism of DHA inhibiting T. gondii growth and its possible drug combinations are described. DHA potently inhibited T. gondii with a half-maximal effective concentration (EC50) of 0.22 μM. DHA significantly increased the ROS level of parasites and decreased the mitochondrial membrane potential, which could be reversed by ferroptosis inhibitors (DFO). Moreover, the ferroptosis inducer RSL3 inhibited T. gondii with an EC50 of 0.75 μM. In addition, RSL3 enhanced the DHA-induced ROS level, and the combination of DHA and RSL3 significantly increased the anti-Toxoplasma effect as compared to DHA alone. In summary, we found that DHA-induced ROS accumulation in tachyzoites may be an important cause of T. gondii growth inhibition. Furthermore, we found that the combination of DHA and RSL3 may be an alternative to toxoplasmosis. These results will provide a new strategy for anti-Toxoplasma drug screening and clinical medication guidance.

Recent Advances in Biochemistry and Molecular Biology of Infectious Diseases

“…In combination, DHA and RSL3 significantly increased the anti-Toxoplasma effect compared to DHA alone. In summary, the paper suggests that combining DHA and RSL3 may be an alternative treatment for toxoplasmosis [11].…”

“…Toxoplasma gondii is a widespread intracellular pathogen that infects humans and various animals. Huang et al [11], studying the reposition of drugs, demonstrated that dihydroartemisinin (DHA), an effective anti-malarial drug, can also inhibit the growth of T. gondii with a half-maximal effective concentration (EC50) of 0.22 µM. DHA significantly increases parasites' ROS levels and decreases the mitochondrial membrane potential, which could be reversed by ferroptosis inhibitors (DFO).…”

Molecular mechanisms of mitochondria-mediated ferroptosis: a potential target for antimalarial interventions

“…Additionally, the potency of the frontline antimalarial compound dihydroartemisinin against both cancer and Plasmodium is attributed to its involvement in ferroptosis-mediated processes ( Du et al, 2019 ; Li et al, 2022 ; Dokunmu et al, 2023 ). According to Huang et al (2022) , ferroptosis was implicated in the significant growth inhibition of Toxoplasma gondii , an apicomplexan parasite.…”

Anti-Mitochondrial and Insecticidal Effects of Artemisinin against Drosophila melanogaster

“…ART is a unique natural product containing a pharmacologically relevant endoperoxide bridge ( Figure 1 A) situated in the backbone structure of a sesquiterpene lactone [ 1 , 2 , 3 ]. In addition to its prominent effects as an antimalarial drug, ART also exhibits activities against other parasites such as Toxoplasma [ 4 ], Leishmania [ 5 ], Clonorchis [ 6 ], Schistosoma [ 7 ], and even some cancer cells [ 8 , 9 ] and viruses [ 10 , 11 ], albeit with a lower efficacy.…”