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Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene-expression profiling

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Item Type:Article
Title:Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene-expression profiling
Creators Name:van Noort, V. and Schoelch, S. and Iskar, M. and Zeller, G. and Ostertag, K. and Schweitzer, C. and Werner, K. and Weitz, J. and Koch, M. and Bork, P.
Abstract:Drug-induced gene-expression profiles that invert disease profiles have recently been illustrated to be a starting point for drug repositioning. In this study, we validate this approach and focus on prediction of novel drugs for colorectal cancer, for which there is a pressing need to find novel antimetastatic compounds. We computationally predicted three novel and still unknown compounds against colorectal cancer: citalopram (an antidepressant), troglitazone (an antidiabetic), and enilconazole (a fungicide). We verified the compounds by in vitro assays of clonogenic survival, proliferation, and migration and in a subcutaneous mouse model. We found evidence that the mode of action of these compounds may be through inhibition of TGF{beta} signaling. Furthermore, one compound, citalopram, reduced tumor size as well as the number of circulating tumor cells and metastases in an orthotopic mouse model of colorectal cancer. This study proposes citalopram as a potential therapeutic option for patients with colorectal cancer, illustrating the potential of systems pharmacology.
Keywords:Antineoplastic Agents, Chromans, Citalopram, Colorectal Neoplasms, Gene Expression Profiling, HCT116 Cells, HT29 Cells, Imidazoles, Inbred NOD Mice, Neoplastic Cells, Circulating, Signal Transduction, Thiazolidinediones, Transcriptome, Transforming Growth Factor beta, Xenograft Model Antitumor Assays, Animals, Mice
Source:Cancer Research
ISSN:0008-5472
Publisher:American Association for Cancer Research (U.S.A.)
Volume:74
Number:20
Page Range:5690-5699
Date:15 October 2014
Official Publication:https://doi.org/10.1158/0008-5472.CAN-13-3540
PubMed:View item in PubMed

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