Mp84-17 luteolin has therapeutic potential through the regulation of oxidative stress in castration-resistant prostate cancer

INTRODUCTION AND OBJECTIVES: Reactive oxygen species (ROS) have been identified as important chemical mediators of cell growth and differentiation, and the glutathione redox system is the main mechanism protecting against the damage caused by ROS in human body. In previous study, we established a new castration resistant prostate cancer (CRPC) animal model. Results of cDNA microarray analysis using this model revealed that glutathione peroxidase 2 (GPX2) had higher expression in CRPC. In this study, we investigated the role of the glutathione redox system in CRPC and the therapeutic potential of the antioxidant properties of luteolin. METHODS: (i) GPX2 siRNA and negative control siRNA (NC) were used to transfect castration resistant PCai1 and PC3 cells, respectively. After transfection, we investigated the proliferation rate and ROS levels through cell counts, DCFH assay, western blotting, and flow cytometry. (ii) siRNA or NC transfected cells were subcutaneously implanted into normal and castrated nude mice. Three weeks after implantation, the mice were sacrificed, and the subcutaneous tumors were isolated. (iii) The effects of luteolin on cell proliferation and apoptosis in PCai cells and on tumor growth of the subcutaneously implanted PCai1 cells in nude mice were analyzed. RESULTS: (i) Silencing of Gpx2 caused significant growth inhibition of PCai1 and PC3 cells, and the DCFH assay revealed that intracellular ROS were significantly elevated in the siRNA treated groups. The decrease in proliferation rate in the siRNA group was attributed to cyclin B1 dependent cell cycle arrest as assessed with flowcytometry. (ii) On PCai1 implantation in nude mice, the tumor growth of PCai1 was significantly inhibited by silencing Gpx2 in the castrated nude mice. (iii) Luteolin suppressed the cell proliferation in a dose dependent manner in vitro, and inhibited tumor growth in a xenograft model via induction of apoptosis and downregulation of Gpx2. CONCLUSIONS: These results suggest that GPX2 plays an important role in cell growth in the presence of ROS in prostate cancer, and the glutathione redox system can regulate cancer cell growth in castration environment. GPX2 expression may be a therapeutic target in CRPC. Luteolin may be a potentially effective chemotherapeutic agent for CRPC via regulation of expression of GPX2 and induction of apoptosis.