title: Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene-expression profiling.
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 TGFβ 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.
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse, Heidelberg, Germany. Centre of Microbial and Plant Genetics, KU Leuven, Kasteelpark Arenberg, Leuven, Belgium.
authors.forename: Vera
authors.initials: V
authors.lastname: van Noort
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schölch
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse, Heidelberg, Germany.
authors.forename: Murat
authors.initials: M
authors.lastname: Iskar
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse, Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Zeller
authors.affiliation: Department of General, Gastrointestinal and Transplant Surgery, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Ostertag
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Schweitzer
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Werner
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. bork@embl.de Moritz.Koch@uniklinikum.
authors.forename: Moritz
authors.initials: M
authors.lastname: Koch
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse, Heidelberg, Germany. Max-Delbrück-Centre (MDC) for Molecular Medicine, Berlin, Germany. bork@embl.de Moritz.Koch@uniklinikum.
authors.forename: Peer
authors.initials: P
authors.lastname: Bork
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002839:Chromans / Q000494:pharmacology / Q000627:therapeutic use; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D016688:Mice, Inbred NOD; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000502:physiology; D000077288:Troglitazone; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D007093:Imidazoles; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D015283:Citalopram; C017435:enilconazole; D000077288:Troglitazone