Fluoxetine inhibits the extracellular signal regulated kinase pathway and suppresses growth of cancer cells.
Fluoxetine (FLX) is a widely prescribed antidepressant. Concerns were raised about the potential impact of FLX on cancer growth, because FLX was shown to promote development of breast cancer in rodents. Here we studied the effect of FLX on tumor growth in lung (A549), colon (HT29), neuroblastoma (SKNAS), medulloblastoma/rhabdomyosarcoma (TE671), astrocytoma (MOGGCCM) and breast (T47D) cancer cells and explored potential mechanisms of its action. In our study, FLX reduced growth of cancer cells in vitro in a concentration dependent manner. The antiproliferative effect of FLX was already evident after 24 hours exposure and more pronounced at 96 hours. We demonstrate that FLX inhibits phosphorylation of ERK1/2 kinases in a time and concentration-dependent manner, followed by reduced phosphorylation of transcription factor c-Myc in A549 and HT29 cells. After treatment with FLX, A549 and HT29 cells demonstrated concentration-dependent decrease in the expression of c-fos, c-jun, cyclin A, cyclin D1, and increased expression of p21(waf1) and p53 genes, which resulted in slowing of the cell cycle progression. We suggest that these changes could be responsible for observed inhibition of cancer cell proliferation during FLX treatment in vitro.
Department of Pediatric Neurology, Children's Hospital, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Dresden, Germany. andrzej.stepulak@uniklinikum-dresden.de
Andrzej
A
Stepulak
Wojciech
W
Rzeski
Marco
M
Sifringer
Katja
K
Brocke
Alexander
A
Gratopp
Krzysztof
K
Kupisz
Lechoslaw
L
Turski
Chrysanthy
C
Ikonomidou
D000928:Antidepressive Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism
D000928:Antidepressive Agents; D018797:Cell Cycle Proteins; D011985:Receptors, Serotonin; D005473:Fluoxetine; D012701:Serotonin; D048049:Extracellular Signal-Regulated MAP Kinases