Fluoxetine increases extracellular levels of 3‐methoxy‐4‐hydroxyphenylglycol in cultured COLO320 DM cells

Abstract

Fluoxetine (Prozac) is a serotonin reuptake inhibitor. It increases extracellular levels of serotonin and is used in relieving the depressive symptoms of cancer patients. It has been reported that the drug may enhance the growth of certain cancer cells. This study investigates whether fluoxetine enhances the growth of a human colon cancer cell line (COLO320 DM) and if it affects the extracellular levels of serotonin or its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) and other monoamines and metabolites at two cell densities. The extracellular levels of serotonin, 5-HIAA and other monoamines and metabolites were measured simultaneously by high performance liquid chromatography from cell-culture media after incubation of cells both with and without fluoxetine for 3 days. The viability of COLO320 DM cells was evaluated using 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). At low cell densities (1.25x10(5) cells ml-1), fluoxetine at 1-10 microM significantly increased the extracellular levels of serotonin (p<0.005), 5-HIAA (p<0.005), and 3-methoxy-4-hydroxyphenylglycol (MHPG; p<0.001) as compared to the controls. Fluoxetine at 10-100 microM significantly inhibited the growth of COLO320 DM (p<0.005). At high cell densities (2x10(6) cells ml-1), fluoxetine at 1-10 microM significantly increased the extracellular levels of MHPG (p<0.01), and at 10 microM it significantly increased the extracellular levels of 5-HIAA (p<0.05). Fluoxetine at 100 microM significantly inhibited the growth of the cells (p<0.0001). These results suggest that fluoxetine at 1 microM of effective concentration may increase the extracellular levels MHPG, in addition to serotonin and 5-HIAA levels, yet not inhibit the growth of COLO320 DM.

Fluoxetine inhibits the extracellular signal regulated kinase pathway and suppresses growth of cancer cells

“…33 It has been demonstrated that fluoxetine can inhibit 11,35 or activate ERK1/2, 36,37 depending on cell type and cellular context. It has also been reported that FLX inhibited proliferation in cancer cell lines, including prostate carcinoma cells, 20 colon carcinoma, 38,39 and induced apoptosis in Burkit Lymphoma cells, 40 rat glioma and human neuroblastoma cell lines. 41 However, normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to FLX-induced cell death, 40 which makes FLX a potentially welltolerated agent with anti-cancer action.…”

“…Concerns were raised about the tumor-promoting potential of FLX when it was reported that clinically relevant doses of FLX accelerated the growth of mammary tumors in rodents. 43 However, later studies revealed an opposite effect, showing that FLX inhibits proliferation of several cancer cell lines, 20,[38][39][40] including also MCF-7 mammary cancer cells. 44 The mechanism of antiproliferative action of FLX on cancer cells is not clear.…”

Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives

“…Newer studies using electron microscopy immunochemistry proposed serotonin as a carcinogenic substance in colon cancer differentiation [74]. Furthermore, a decreased metabolic activity and growth of cultured human colorectal carcinoma after treatment with SSRIs was reported [75]. Recently, a large epidemiological study described a reduced risk of colorectal cancer after daily intake of SSRIs compared with non-users of such antidepressants [76].…”

Antidepressant fluoxetine and its potential against colon tumors

“…The anti-tumor proliferative effects of FLX [40,56,92,93] have been related to different causes, such as delays in cell-cycle progression by inhibiting DNA synthesis and also to a possible binding directly to DNA via groove mode and high attraction force [58,[87][88][89][90]94] . On a molecular level, FLX was shown to arrest breast tumor cells at G0/G1 phase by disrupting skp2-CKS1 assembly, which is required to enable cell cycle progression [91] .…”