title: Antiproliferative effects of fluoxetine on colon cancer cells and in a colonic carcinogen mouse model.
abstract: The antidepressant fluoxetine has been under discussion because of its potential influence on cancer risk. It was found to inhibit the development of carcinogen-induced preneoplastic lesions in colon tissue, but the mechanisms of action are not well understood. Therefore, we investigated anti-proliferative effects, and used HT29 colon tumor cells in vitro, as well as C57BL/6 mice exposed to intra-rectal treatment with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as models. Fluoxetine increased the percentage of HT29 cells in the G(0)/G(1) phase of cell-cycle, and the expression of p27 protein. This was not related to an induction of apoptosis, reactive oxygen species or DNA damage. In vivo, fluoxetine reduced the development of MNNG-induced dysplasia and vascularization-related dysplasia in colon tissue, which was analyzed by histopathological techniques. An anti-proliferative potential of fluoxetine was observed in epithelial and stromal areas. It was accompanied by a reduction of VEGF expression and of the number of cells with angiogenic potential, such as CD133, CD34, and CD31-positive cell clusters. Taken together, our findings suggest that fluoxetine treatment targets steps of early colon carcinogenesis. This confirms its protective potential, explaining at least partially the lower colon cancer risk under antidepressant therapy.
authors.affiliation: Department of Pathology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Kannen
authors.forename: Henning
authors.initials: H
authors.lastname: Hintzsche
authors.forename: Dalila L
authors.initials: DL
authors.lastname: Zanette
authors.forename: Wilson A
authors.initials: WA
authors.lastname: Silva
authors.forename: Sérgio B
authors.initials: SB
authors.lastname: Garcia
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D017382:Reactive Oxygen Species; D005473:Fluoxetine; D050760:Cyclin-Dependent Kinase Inhibitor p27