Drug-induced cytotoxicity prediction in muscle cells, an application of the Cell Painting assay

Abstract

AbstractIn silicotoxicity prediction offers the chance of reducing or replacing most animal testing through the integration of large experimental assay datasets with the appropriate computational approaches. The use of Cell Painting to detect various phenotypic changes induced by chemicals is emerging as a powerful technique in toxicity prediction. However, most Cell Painting approaches use cancer cells that are less relevant for many toxicological endpoints, which may limit the usefulness of this data. In this study, a myoblast cell line is used to characterize cellular responses to a panel of 30 known myotoxicants. In place of traditional structural descriptors, here each perturbation is described by a fingerprint of calculated properties, deducted from the intensity, shape, or texture of individual cells. We show that these kinds of descriptors convey information to allow the prediction of the cellular viability and fate of cells in myoblasts and differentiated myotubes of the C2C12 cell line, and the clustering of drugs by their cytotoxicity responses.Author SummaryStudying the toxicity of chemical compounds and drugs is crucial to avoid potentially lethal adverse effects of commercialized products, but also to detect the unsuspected toxicity of existing drugs. While these assays traditionally rely on animal models raising important ethical concerns, a need forin vitroandin silicomodels is present and increasing in recent years. We here propose a predictive model capable of predicting the values of a cell viability assay using cell morphology profiles captured with a microscopy experiment. This model predicts the healthiness of muscle cells treated with 30 compounds suspected to induce muscular damage or even myopathies in humans. We also use these profiles to find an interesting morphological similarity between two different classes of drugs: statins (used for cholesterol treatments) and tyrosine kinase inhibitors (anti-cancer drugs). This analysis opens a new perspective for understanding the mechanisms responsible for drug-induced muscular toxicity, an area of toxicology that is currently under-researched.