Anti-Cancer Effects of Artesunate in Human 3D Tumor Models of Different Complexity

Abstract

The anti-malaria drug Artesunate (ART) shows strong anti-cancer effects in vitro; however, it shows only marginal treatment results in clinical cancer studies. In this study, ART was tested in preclinical 3D cancer models of increasing complexity using clinically relevant peak plasma concentrations to obtain further information for translation into clinical use. ART reduced cell viability in HCT-116 and HT-29 derived cancer spheroids (p < 0.001). HCT-116 spheroids responded dose-dependently, while HT-29 spheroids were affected more strongly by ART than by cytostatics (p < 0.001). HCT-116 spheroids were chemo-sensitized by ART (p < 0.001). In patient-derived cancer spheroids (PDCS), ART led to inhibition of cell viability in 84.62% of the 39 samples tested, with a mean inhibitory effect of 13.87%. Viability reduction of ART was 2-fold weaker than cytostatic monotherapies (p = 0.028). Meanwhile, tumor-stimulation of up to 16.30% was observed in six (15.38%) PDCS-models. In 15 PDCS samples, ART modulated chemotherapies in combined testing, eight of which showed chemo-stimulation (maximum of 36.90%) and seven chemo-inhibition (up to 16.95%). These results demonstrate that ART’s anti-cancer efficacy depends on the complexity of the tumor model used. This emphasizes that cancer treatment with ART should be evaluated before treatment of the individual patient to ensure its benefits and prevent unwanted effects.

Autocatalytic Artesunate Coordinated ZIF-8 Nanoplatforms with Metal-Polyphenol Network Coating for Targeted Tumor Chemodynamic Therapy

“…Artesunate (Art) is a semisynthetic sesquiterpene lactone compound that has been widely used as a first-line drug for malaria treatment. − Compared with chemical drugs, Art as a derivative of artemisinin has relatively lower side effects and better pharmacokinetics. In addition to malaria treatment, Art has been also demonstrated to display antitumor effect possibly by inducing oxidative damage, cell cycle arrest, as well as signaling pathway disruption. − Mounting evidence has shown that the peroxide-bridge (R–OO–R′) structure inside Art exerted a crucial role in the therapeutic effects. Specifically, the peroxide-bridge can react with ferrous ions via Fenton reaction to produce carbon-center radicals or reactive oxygen species (ROS), thereby resulting in irreversible oxidative damage to tumor cells. − Given this feature, Art was considered as a potential CDT candidate for tumor therapy.…”

Novel artesunate-metformin conjugate inhibits bladder cancer cell growth associated with Clusterin/SREBP1/FASN signaling pathway

“…Artesunate is a water solubility derivative of artemisinin and the most effective drug for the treatment of severe malaria [ 13 ]. In recent years, its anti-tumor effects were explored as well [ 14 , 15 ]. Thus, introducing the artesunate group to metformin moiety may improve its anti-bladder cancer activity.…”

“…Thus, introducing the artesunate group to metformin moiety may improve its anti-bladder cancer activity. Along with this thought, we [ 15 ] designed and obtained a new artesunate dimer triazine derivative AM2 by esterification of artesunate and metformin.…”

Formulation and Characterization of GDL-Based Artesunate Solid Lipid Nanoparticle

“…Heme present in the food vacuole of plasmodium interacts with the endoperoxide bridge of ART and activates it. The generation of reactive oxygen species subsequently binds to membrane protein and induces lipid peroxidation and, ultimately lysis of the plasmodium parasite [9]. Short half-life and rapid metabolism; however, limit the application of ART.…”