Abstract
Polypharmacology (the ability of a drug to affect more than one molecular target) is considered a basic property of many therapeutic small molecules. Herein, we used a chemical genomics approach to systematically analyze polypharmacology by integrating several analytical tools, including the LINCS (Library of Integrated Cellular Signatures), STITCH (Search Tool for Interactions of Chemicals), and WebGestalt (WEB-based GEne SeT AnaLysis Toolkit). We applied this approach to identify functional disparities between two cytidine nucleoside analogs: azacytidine (AZA) and decitabine (DAC). AZA and DAC are structurally and mechanistically similar DNA-hypomethylating agents. However, their metabolism and destinations in cells are distinct. Due to their differential incorporation into RNA or DNA, functional disparities between AZA and DAC are expected. Indeed, different cytotoxicities of AZA and DAC toward human colorectal cancer cell lines were observed, in which cells were more sensitive to AZA. Based on a polypharmacological analysis, we found that AZA transiently blocked protein synthesis and induced an acute apoptotic response that was antagonized by concurrently induced cytoprotective autophagy. In contrast, DAC caused cell cycle arrest at the G2/M phase associated with p53 induction. Therefore, our study discriminated functional disparities between AZA and DAC, and also demonstrated the value of this chemical genomics approach that can be applied to discover novel drug action mechanisms.
Highlights
Many therapeutic drugs generally exhibit actions on more than one molecular target, which is a phenomenon known as polypharmacology [1]
Our previous study successfully identified novel action mechanisms of the Chinese herbal medicine, berberine, using a gene expression signature-based approach [4]. This approach integrates the Connectivity MAP (CMAP) that collects gene-expression profiles from cultured human cells treated with small molecules [5], and the Search Tool for Interactions of Chemicals (STITCH) that explores known www.impactjournals.com/oncotarget and predicted interactions of chemicals and proteins by evidence derived from experiments, databases, and the literatures [6]
CMAP, a chemical genomics database that collects gene-expression profiles from cultured human cells treated with small molecules, can be used to find connections among small molecules that share common action mechanisms [5]
Summary
Many therapeutic drugs generally exhibit actions on more than one molecular target, which is a phenomenon known as polypharmacology [1]. Our previous study successfully identified novel action mechanisms of the Chinese herbal medicine, berberine, using a gene expression signature-based approach [4] This approach integrates the Connectivity MAP (CMAP) that collects gene-expression profiles from cultured human cells treated with small molecules [5], and the Search Tool for Interactions of Chemicals (STITCH) that explores known www.impactjournals.com/oncotarget and predicted interactions of chemicals and proteins by evidence derived from experiments, databases, and the literatures [6]. More and more biomedical databases and analytical tools have been developed in recent years, which provide easy and open access to masses of accumulated data [3] Integration of these resources will be highly useful in the field of polypharmacology
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