8-Farnesyloxycoumarin induces apoptosis in PC-3 prostate cancer cells by inhibition of 15-lipoxygenase-1 enzymatic activity

Abstract

Prostate cancer is the second most common cancer in men worldwide. Overexpression of 15-lipoxygenase-1 (15-LOX-1) has been reported in prostate cancer patients. This study aimed to investigate the cytotoxic and anticancer effects of 8-farnesyloxycoumarin (8f), a prenylated coumarin, by inhibition of 15-LOX-1 activity, in prostate cancer cells. The activity of 15-LOX-1 and the inhibitory effects of 8f on this enzyme were first assessed in PC-3 and DU145 prostate cancer cells. The MTT assay was used to examine the cytotoxicity effects of 8f on PC-3 cells following 15-LOX-1 inhibition. To determine the type of cell death, chromatin condensation and DNA damage were examined by DAPI staining and comet assay, respectively. Furthermore, the effects of 8f on the cell cycle were evaluated by PI staining and flow cytometry. The activity of 15-LOX-1 was determined to be higher in PC-3 compared with DU145 cells; thus, this cell line was selected for further experiments. 8f induced cell death in PC-3 cells in a dose-dependent and time-dependent manner, with IC50 values similar to cisplatin, which was used as a control. However, 8f did not significantly affect the viability of HFF3, human foreskin fibroblast cells, under identical conditions. The appearance of apoptotic cells after 8f treatment was confirmed by the presence of PC-3 cells containing condensed chromatin as shown by DAPI staining. The comet assay indicated the induction of DNA damage in cancerous cells compared with normal cells. In addition, 8f induced a potent G1 cell-cycle arrest in PC-3 cells. Our results showed that the antitumor effects of 8f on PC-3 cells were promoted by apoptosis induction, probably via inhibition of 15-LOX-1 activity, thus suggesting that 8f may have therapeutic value in prostate cancer treatment.