TY - JOUR
T1 - Pathway-Based Drug Repositioning for Cancers
T2 - Computational Prediction and Experimental Validation
AU - Iwata, Michio
AU - Hirose, Lisa
AU - Kohara, Hiroshi
AU - Liao, Jiyuan
AU - Sawada, Ryusuke
AU - Akiyoshi, Sayaka
AU - Tani, Kenzaburo
AU - Yamanishi, Yoshihiro
N1 - Funding Information:
This work is supported by JST PRESTO Grant Number JPMJPR15D8, and JSPS KAKENHI Grant Number 15K14980. This work was also supported by the Shin-Nihon of Advanced Medical Research.
Funding Information:
*E-mail: yamani@bio.kyutech.ac.jp. ORCID Michio Iwata: 0000-0001-6500-4692 Author Contributions MI performed all computational analyses. HK and LH performed all experiments. JL prepared samples for experiments. RS prepared molecular data. MI, HK, LH, SA, KT, and YY wrote the manuscript. All authors approved the manuscript. Notes The authors declare the following competing financial interest(s): Project Division of ALA Advanced Medical Research, the Institute of Medical Science at the University of Tokyo is supported by grants from SBI Pharmaceutical. Co, Ltd. and Shinnihonseiyaku Co. The terms of this arrangement have been reviewed and approved by the University of Tokyo in accordance with its conflict of interest policies. Calculated scores for all the drugs for which drug-induced gene expression data were available in the LINCS database are available on the following Web site: http://labo.bio.kyutech.ac. jp/~yamani/pathwayDR/.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/11/8
Y1 - 2018/11/8
N2 - Developing drugs with anticancer activity and low toxic side-effects at low costs is a challenging issue for cancer chemotherapy. In this work, we propose to use molecular pathways as the therapeutic targets and develop a novel computational approach for drug repositioning for cancer treatment. We analyzed chemically induced gene expression data of 1112 drugs on 66 human cell lines and searched for drugs that inactivate pathways involved in the growth of cancer cells (cell cycle) and activate pathways that contribute to the death of cancer cells (e.g., apoptosis and p53 signaling). Finally, we performed a large-scale prediction of potential anticancer effects for all the drugs and experimentally validated the prediction results via three in vitro cellular assays that evaluate cell viability, cytotoxicity, and apoptosis induction. Using this strategy, we successfully identified several potential anticancer drugs. The proposed pathway-based method has great potential to improve drug repositioning research for cancer treatment.
AB - Developing drugs with anticancer activity and low toxic side-effects at low costs is a challenging issue for cancer chemotherapy. In this work, we propose to use molecular pathways as the therapeutic targets and develop a novel computational approach for drug repositioning for cancer treatment. We analyzed chemically induced gene expression data of 1112 drugs on 66 human cell lines and searched for drugs that inactivate pathways involved in the growth of cancer cells (cell cycle) and activate pathways that contribute to the death of cancer cells (e.g., apoptosis and p53 signaling). Finally, we performed a large-scale prediction of potential anticancer effects for all the drugs and experimentally validated the prediction results via three in vitro cellular assays that evaluate cell viability, cytotoxicity, and apoptosis induction. Using this strategy, we successfully identified several potential anticancer drugs. The proposed pathway-based method has great potential to improve drug repositioning research for cancer treatment.
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U2 - 10.1021/acs.jmedchem.8b01044
DO - 10.1021/acs.jmedchem.8b01044
M3 - Article
C2 - 30371064
AN - SCOPUS:85056341912
SN - 0022-2623
VL - 61
SP - 9583
EP - 9595
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -
