Artemisinin toxicity in HepG2 liver carcinoma cells is linked to protein network in host and molecular interactions with cellular drug targets

Artemisinin treatment at high concentration or prolonged period is exhibiting severe toxicity in liver, kidney and cardio toxicity. Artemisinin is killing HepG2 liver carcinoma cells with an IC₅₀ of 17.33 ± 2.64 μM and cells are showing distorted morphology with appearance of holes on the cell surface. The cells are leaky and releasing the marker enzymes into the culture supernatant. Surprisingly, Artemisinin is inhibiting cell migration potentials in a dose-dependent manner. Drug Bank and Swiss target prediction indicate that the drug molecule is interacting with 118 protein nodes recognizing different pharmacological sites on the molecule. Gene ontology enrichment analysis indicate presence of protein belonging to 266 biological processes, 68 cellular components and 90 molecular functions. KEGG analysis predicts off-target proteins to disrupt cell-cycle, apoptosis, autophagy and other biological pathways. The protein-protein interaction network comprises 104 nodes and 30 edges. Artemisinin is fitting into these proteins and Artermisnin-protein complex is stable under the molecular dynamic simulation. Cells treated with Artemisinin is exhibiting disturbance of cell-cycle, apoptosis following intrinsic pathway and modulation of cyclin D1, activation of MLKL, caspase-8, caspase-3 and degradation of PARP. Artemisinin is curing malaria but current study highlight the importance of off-target effects to understand the liver toxicity in patients.