Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:32402.

Systematic discovery of drug action mechanisms by an integrated chemical genomics approach: identification of functional disparities between azacytidine and decitabine

Yao-Yu Hsieh, Tsui-Chin Huang, Hsiang-Ling Lo, Jyun-Yan Jhan, Shui-Tein Chen and Pei-Ming Yang _

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Oncotarget. 2016; 7:27363-27378. https://doi.org/10.18632/oncotarget.8455

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Abstract

Yao-Yu Hsieh1,2,5, Tsui-Chin Huang1,3, Hsiang-Ling Lo1,3, Jyun-Yan Jhan1,3, Shui-Tein Chen1,4, Pei-Ming Yang1,3

1PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

2Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

3Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

4Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

5Department of Internal Medicine, Division of Hematology and Oncology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Correspondence to:

Pei-Ming Yang, e-mail: [email protected]

Keywords: colorectal cancer, DNMT inhibitor, drug repurposing, polypharmacology, systems pharmacology

Received: December 05, 2015     Accepted: March 16, 2016     Published: March 29, 2016

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.


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