Identification of molecular pathways involved in the anti-liver cancer activity of madecassic acid

Natural products are a time-tested source of medicinal compounds, and there is huge interest in discovery of new drugs from plant sources. However, in many cases the effects are not as well understood, strong, or selective, as would be hoped. An example of this is madecassic acid (MA), which has promising activity against liver cancer, activity which can be improved through chemical modifications, although a molecular understanding of its mechanism of action is unknown. In this report we have used chemical proteomics to identify the proteins with which madecassic interacts in liver cancer cells, and used RNAseq to support those findings, as well as showing more precisely how chemical modifications can focus and amplify MA activity. Our results show that madecassic acid interacts with a number of proteins relating to metabolism, nucleic acid processing, and protein folding, which have been previously identified as linked to liver cancer. This provides a route from phenotypic- to target based-drug discovery and develop new potential treatments for a globally challenging disease.