Development of Orthogonal Linear Separation Analysis (OLSA) to Decompose Drug Effects into Basic Components.

Drugs have multiple, not single, effects. Decomposition of drug effects into basic components helps us to understand the pharmacological properties of a drug and contributes to drug discovery. We have extended factor analysis and developed a novel profile data analysis method: orthogonal linear separation analysis (OLSA). OLSA contracted 11,911 genes to 118 factors from transcriptome data of MCF7 cells treated with 318 compounds in a Connectivity Map. Ontology of the main genes constituting the factors detected significant enrichment of the ontology in 65 of 118 factors and similar results were obtained in two other data sets. In further analysis of the Connectivity Map data set, one factor discriminated two Hsp90 inhibitors, geldanamycin and radicicol, while clustering analysis could not. Doxorubicin and other topoisomerase inhibitors were estimated to inhibit Na+ /K+ ATPase, one of the suggested mechanisms of doxorubicin-induced cardiotoxicity. Based on the factor including PI3K/AKT/mTORC1 inhibition activity, 5 compounds were predicted to be novel inducers of autophagy, and other analyses including western blotting revealed that 4 of the 5 actually induced autophagy. These findings indicate the potential of OLSA to decompose the effects of a drug and identify its basic components.