Effect of repurposed drugs on the cellular properties of childhood cancer: in vitro & in silico studies
Rhabdoid tumours (RT) are a rare form of childhood cancer which is known to affect infants under the age of 1 year. Survival rate is a major problem with only 31% of those who are diagnosed living to 1 years old. In this research extracranial RT from the A204 cell line was investigated for its interaction with the drugs loratadine and carvacrol. Drug-cell interactions were probed at a single cell level and biological changes within the cell were monitored experimentally through the cell viability MTT assay. Biological changes were also monitored computationally using molecular dynamics (MD) simulations. Three models for cell membranes were proposed, one model for cancer membrane and two models for healthy membranes. All models comprise three lipid types, the most abundant in cell plasma membranes, 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC), palmitoylsphingomyelin (PSM) and cholesterol (CHOL) with different compositions. Results of the experimental MTT assays showed that while both loratadine and carvacrol are cytotoxic against the A204 cells, loratadine produced the greater cytotoxic effect. Additionally, the drugs produced a synergistic effect when they were used in combination. MD simulation results have shown that individually both drugs permeate the flexible cancer membrane and not the rigid healthy membrane. Similar results are found when used in combination as both drugs again permeate the cancer membrane and not the rigid healthy membrane. Area per lipid increased when drugs permeated the membrane, while no change was found when the drugs did not permeate the membrane. Changes were also detected in relation to tail order of the cancer membrane possibly due to its overall disordered structure resulting in higher flexibility and permeability to the drugs, while the rigid healthy membrane did not allow permeation of drugs. These findings suggest and reiterate the potential benefits of using non-cancer drugs for the treatment of childhood RT.
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