TY - JOUR
T1 - Systematic discovery of drug action mechanisms by an integrated chemical genomics approach
T2 - Identification of functional disparities between azacytidine and decitabine
AU - Hsieh, Yao Yu
AU - Huang, Tsui Chin
AU - Lo, Hsiang Ling
AU - Jhan, Jyun Yan
AU - Chen, Shui Tein
AU - Yang, Pei Ming
PY - 2016/5/10
Y1 - 2016/5/10
N2 - 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.
AB - 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.
KW - Colorectal cancer
KW - DNMT inhibitor
KW - Drug repurposing
KW - Polypharmacology
KW - Systems pharmacology
UR - http://www.scopus.com/inward/record.url?scp=84968719159&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84968719159&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.8455
DO - 10.18632/oncotarget.8455
M3 - Article
C2 - 27036028
AN - SCOPUS:84968719159
SN - 1949-2553
VL - 7
SP - 27363
EP - 27378
JO - Oncotarget
JF - Oncotarget
IS - 19
ER -