| Abstract |
Fluoxetine (FLX) is a commonly antidepressant for oral administration and belonging to the selective serotonin reuptake inhibitors (SSRI), which is used for the treatment of Major Depressive Disorder (MDD), Obsessive Compulsive Disorder (OCD) and panic disorder. Recently has been reported that fluoxetine affects on the cell growth, apoptosis and cell cycle in various types of cancer. Hence, we want to investigate whether FLX has anti-tumor effects on human pancreatic ductal adenocarcinoma. We found that of pancreatic cancer cells treatment with FLX significantly reduced cell proliferation/viability, and cell cycle analysis revealed that exposure of pancreatic cancer cells to FLX resulted in increased Sub G1 peak. Further, western blot analysis found that an increase of PARP cleavage and caspase 3 activity after FLX treatment that confirmed fluoxetine induced apoptosis at molecular level. Quantitative real-time PCR(q-PCR) analysis indicated that FLX down-regulate expression of cyclinD, cyclin B1,CDK1 and CDK2, and up-regulate expression of p27 and P19. Next, we confirm the in vivo efficiency of fluoxetine therapy on our GEM mouse model of human pancreatic cancer in vivo and we observed FLX induces apoptosis in mice PDAC tumors and inhibits tumor growth in vivo. In addition, immunohistochemistry stain (IHC) data showed that FLX suppress EGFR and Notch-1 and accumulates P27 protein expression. Finally, we combine the treatment of Fluoxetine and anticancer drugs to have synergistic effects on the inhibition cancer cell growth in vitro. Therefore, we propose that effects of Fluoxetine mediated antitumor effect may be contributing to the alterations of tumor cell proliferation and apoptosis thus resulting in the inhibition of PDAC progression. |
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