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Oncostatic effects of fluoxetine in experimental colon cancer models
Vinicius Kannen1, Sergio Britto Garcia2, Wilson A Silva3
1Department of Toxicology, University of Wuerzburg, Germany.
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.
Insights
The antidepressant fluoxetine (FLX) may reduce colon cancer risk by impairing tumor cell energy production and proliferation, particularly in low-oxygen conditions. This mechanism leads to decreased tumor growth and blood vessel formation in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Colon cancer is a prevalent human malignancy.
- Fluoxetine (FLX), an antidepressant, has been anecdotally linked to reduced colon cancer risk, but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the anti-cancer mechanisms of fluoxetine (FLX) in colon cancer models, focusing on its effects on tumor cell proliferation, energy metabolism, and angiogenesis, especially under hypoxic conditions.
Main Methods:
- Colon tumor xenograft models and cell culture experiments were utilized.
- Effects of FLX on tumor growth, proliferation (especially in hypoxic areas), microvessel density, glucose and lactate levels, and mitochondrial function (complexes III and V, membrane potential, ROS production) were assessed.
- Gene expression of MCT4 and cell-cycle checkpoint proteins were analyzed.
Main Results:
- FLX reduced colon tumor xenograft development and proliferation in hypoxic regions.
- FLX treatment decreased tumor microvessel density and augmented intratumoral lactate levels, while downregulating MCT4 gene expression.
- FLX impaired mitochondrial function, reduced mitochondrial membrane potential, inhibited ROS production in complex III, and arrested hypoxic colon tumor cells in the G0/G1 phase by enhancing cell-cycle checkpoint proteins.
Conclusions:
- Fluoxetine (FLX) demonstrates anti-cancer effects by disrupting energy metabolism and cell cycle progression in colon tumor cells, particularly under hypoxia.
- These effects contribute to reduced angiogenesis and tumor shrinkage in preclinical models, suggesting a potential therapeutic role for FLX in colon cancer treatment.
