title: Oncostatic effects of fluoxetine in experimental colon cancer models.
abstract: Colon cancer is one of the most common tumors in the human population. Recent studies have shown a reduced risk for colon cancer in patients given the antidepressant fluoxetine (FLX). The exact mechanism by which FLX might protect from colon cancer remains however controversial. Here, FLX reduced the development of different colon tumor xenografts, as well as proliferation in hypoxic tumor areas within them. FLX treatment also decreased microvessel numbers in tumors. Although FLX did not increase serum and tumor glucose levels as much as the colon chemotherapy gold standard Fluorouracil did, lactate levels were significantly augmented within tumors by FLX treatment. The gene expression of the MCT4 lactate transporter was significantly downregulated. Total protein amounts from the third and fifth mitochondrial complexes were significantly decreased by FLX in tumors. Cell culture experiments revealed that FLX reduced the mitochondrial membrane potential significantly and disabled the reactive oxygen species production of the third mitochondrial complex. Furthermore, FLX arrested hypoxic colon tumor cells in the G0/G1 phase of the cell-cycle. The expression of key cell-cycle-related checkpoint proteins was enhanced in cell culture and in vivo experiments. Therefore, we suggest FLX impairs energy generation, cell cycle progression and proliferation in tumor cells, especially under condition of hypoxia. This then leads to reduced microvessel formation and tumor shrinkage in xenograft models.
authors.affiliation: Department of Toxicology, University of Wuerzburg, Germany. Electronic address: vinicius.kannen@fcfrp.usp.br.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Kannen
authors.affiliation: Department of Pathology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Sergio Britto
authors.initials: SB
authors.lastname: Garcia
authors.affiliation: Center for Cell-Based Therapy, CEPID/FAPESP, Department of Genetics, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Wilson A
authors.initials: WA
authors.lastname: Silva
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Germany.
authors.forename: Romana
authors.initials: R
authors.lastname: Mönch
authors.affiliation: Clinic and Policlinic for Psychiatry and Psychotherapy, University of Wuerzburg, Germany.
authors.forename: Eduardo Joaquim Lopes
authors.initials: EJ
authors.lastname: Alho
authors.affiliation: Clinic and Policlinic for Psychiatry and Psychotherapy, University of Wuerzburg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Heinsen
authors.affiliation: Interdisciplinary Center for Clinical Research, Laboratory for Microarray Applications, University of Wuerzburg, Germany.
authors.forename: Claus-Jürgen
authors.initials: CJ
authors.lastname: Scholz
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, Germany.
authors.forename: Katrin Gertrud
authors.initials: KG
authors.lastname: Heinze
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Germany.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
authors.affiliation: Department of Toxicology, University of Wuerzburg, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D015687:Cell Hypoxia / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005473:Fluoxetine / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D005473:Fluoxetine
keywords: Angiogenesis; Anticancer therapy; Colon cancer; Tumor edge; Tumor perinecrotic areas