Objective: Drug repurposing, the application of existing therapeutics to new indications, holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development. The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases, particularly cancers. Methods: Here, by targeting 4,096 human diseases, including 384 cancers, we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in DrugBank. We performed additional experimental validation for the dominant repurposed drugs in cancer. Results: The overall performance of the model was well supported by cross-validation and literature mining. Focusing on the top-ranked repurposed drugs in cancers, we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments. Because of the distinctive antitumor effects of nifedipine (an antihypertensive agent) and nortriptyline (an antidepressant drug) in prostate cancer, we further explored their underlying mechanisms by using quantitative proteomics. Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication, the cell cycle, and RNA transport. Moreover, in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model. Conclusions: Our predicted results, which have been released in a public database named The Predictive Database for Drug Repurposing (PAD), provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.

Xi Cheng;Wensi Zhao;Mengdi Zhu;Bo Wang;Xuege Wang;Xiaoyun Yang;Yuqi Huang;Minjia Tan;Jing Li

Department of Bioinformatics and Biostatistics,School of Life Sciences and Biotechnology,Shanghai Jiao Tong University,Shanghai 200240,China;The Chemical Proteomics Center and State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,Shanghai Institutes for Biological Sciences,University of Chinese Academy of Sciences,Chinese Academy of Sciences(CAS),Shanghai 200031,China

癌症生物学与医学（英文版）

[1]Xi Cheng;Wensi Zhao;Mengdi Zhu;Bo Wang;Xuege Wang;Xiaoyun Yang;Yuqi Huang;Minjia Tan;Jing Li-.Drug repurposing for cancer treatment through global propagation with a greedy algorithm in a multilayer network)[J].癌症生物学与医学（英文版）,2022(01):74-89

nifedipine,nortriptyline

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