Department of Pathology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14049-900, Brazil.
Toxicol Lett. 2011 Jul 28;204(2-3):134-40. doi: 10.1016/j.toxlet.2011.04.024. Epub 2011 Apr 29.
Fluoxetine (FLX) is a drug commonly used as antidepressant. However, its effects on tumorigenesis remain controversial. Aiming to evaluate the effects of FLX treatment on early malignant changes, we analyzed serotonin (5-HT) metabolism and recognition, aberrant crypt foci (ACF), proliferative process, microvessels, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) expression in colon tissue. Male Wistar rats received a daily FLX-gavage (30mgkg(-1)) and, a single dose of 1,2 dimethylhydrazine (DMH; i.p., 125mgkg(-1)). After 6 weeks of FLX-treatment, our results revealed that FLX and nor-fluoxetine (N-FLX) are present in colon tissue, which was related to significant increase in serotonin (5-HT) levels (P<0.05) possibly through a blockade in SERT mRNA (serotonin reuptake transporter; P<0.05) resulting in lower 5-hydroxyindoleacetic acid (5-HIAA) levels (P<0.01) and, 5-HT2C receptor mRNA expressions. FLX-treatment decreased dysplastic ACF development (P<0.01) and proliferative process (P<0.001) in epithelia. We observed a significant decrease in the development of malignant microvessels (P<0.05), VEGF (P<0.001), and COX-2 expression (P<0.01). These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue, probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events.
氟西汀（FLX）是一种常用的抗抑郁药物。然而，其对肿瘤发生的影响仍存在争议。为了评估 FLX 治疗对早期恶性变化的影响，我们分析了结肠组织中的 5-羟色胺（5-HT）代谢和识别、异常隐窝病灶（ACF）、增殖过程、微血管、血管内皮生长因子（VEGF）和环氧化酶-2（COX-2）的表达。雄性 Wistar 大鼠接受每日 FLX 灌胃（30mgkg(-1))和单次腹腔注射 1,2 二甲基肼（DMH；125mgkg(-1))。FLX 治疗 6 周后，我们的结果表明，FLX 和去氟西汀（N-FLX）存在于结肠组织中，这与 5-HT 水平的显著升高（P<0.05）有关，可能是通过 SERT mRNA（5-羟色胺再摄取转运体；P<0.05）的阻断导致 5-羟吲哚乙酸（5-HIAA）水平降低（P<0.01）和 5-HT2C 受体 mRNA 表达。FLX 治疗降低了上皮异型 ACF 的发育（P<0.01）和增殖过程（P<0.001）。我们观察到恶性微血管的发展显著减少（P<0.05），VEGF（P<0.001）和 COX-2 表达（P<0.01）。这些发现表明，FLX 可能对致癌结肠组织具有肿瘤抑制作用，这可能与其对 5-HT 代谢的调节活性或其减少结肠恶性事件的能力有关。
