Stylosin and some of its synthetic derivatives induce apoptosis in prostate cancer cells as 15-lipoxygenase enzyme inhibitors

Abstract

Overexpression of 15-lipoxygenase-1 (15-LOX-1) enzyme has been reported in prostate tumors, and its expression levels are associated with the degree of cancer malignancy. The aim of this study was to investigate inhibitory effects of stylosin and some similar synthetic monoterpenoids on 15-LOX and also their cytotoxic and anti-cancer activities on prostate cancer cells. Cytotoxicity of compounds was evaluated on prostate cancer cell line "PC-3" and normal human fibroblast "HFF3" cells using AlamarBlue reduction test. The inhibitory effects of the compounds against soybean 15-LOX, a commercially available enzyme, were also assessed. Finally, mechanism of cell death was investigated by flow cytometry. Some of these terpenoids had cytotoxic effects on PC-3 cells, and strong positive correlation was observed between the 15-LOX-1 inhibition potential and the cytotoxicity of the compounds. Moreover, flow cytometry results indicated that apoptosis was the predominant mechanism of induced cell death, which emphasizes the potential of these compounds in prostate cancer therapy. Among studied terpenoids, "fenchyl ferulate" exhibited about three times more cytotoxicity than cisplatin. Strong positive correlation observed between 15-LOX inhibition potential and cytotoxicity of the compounds indicates selective anti-cancer properties of the compounds might be exerted via inhibition of 15-LOX-1 in PC-3 cells. Furthermore, observed cytotoxicity is mediated through apoptosis, which is probably triggered via 15-LOX-1 inhibition.

Keywords: 15-LOX-1; Cytotoxicity; Monoterpenoids; Prostate cancer; Stylosin.