Oncostatic effects of fluoxetine in experimental colon cancer models.

Autor: Kannen V; Department of Toxicology, University of Wuerzburg, Germany. Electronic address: vinicius.kannen@fcfrp.usp.br., Garcia SB; Department of Pathology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil., Silva WA Jr; Center for Cell-Based Therapy, CEPID/FAPESP, Department of Genetics, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil., Gasser M; Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Germany., Mönch R; Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Germany., Alho EJ; Clinic and Policlinic for Psychiatry and Psychotherapy, University of Wuerzburg, Germany., Heinsen H; Clinic and Policlinic for Psychiatry and Psychotherapy, University of Wuerzburg, Germany., Scholz CJ; Interdisciplinary Center for Clinical Research, Laboratory for Microarray Applications, University of Wuerzburg, Germany., Friedrich M; Rudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, Germany., Heinze KG; Rudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, Germany., Waaga-Gasser AM; Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Germany., Stopper H; Department of Toxicology, University of Wuerzburg, Germany.
Jazyk: angličtina
Zdroj: Cellular signalling [Cell Signal] 2015 Sep; Vol. 27 (9), pp. 1781-8. Date of Electronic Publication: 2015 May 22.
DOI: 10.1016/j.cellsig.2015.05.008
Abstrakt: 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.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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