Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Ukjin Kim; C-Yoon Kim; Ji Min Lee; Bokyeong Ryu; Jin Kim; Changsoo Shin; Jae-Hak Park

doi:10.3389/fphar.2019.01517

Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Front Pharmacol. 2020 Jan 16:10:1517. doi: 10.3389/fphar.2019.01517. eCollection 2019.

Authors

Ukjin Kim¹, C-Yoon Kim², Ji Min Lee¹, Bokyeong Ryu¹, Jin Kim¹, Changsoo Shin³, Jae-Hak Park¹

Affiliations

¹ Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
² Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, South Korea.
³ Department of Energy Resources Engineering, Seoul National University, Seoul, South Korea.

Abstract

The United States Food and Drug Administration-approved antipsychotic drug, pimozide, has anticancer activities. However, the role of reactive oxygen species (ROS) in its effect on prostate cancer is not well-known. We examined cell proliferation, colony formation, migration, ROS production, and the expression of antioxidant-related genes after treatment of human prostate cancer PC3 and DU145 cells with pimozide. In addition, histopathology, ROS production, and superoxide dismutase (SOD) activity were analyzed after administering pimozide to TRAMP, a transgenic mouse with prostate cancer. Pimozide increased the generation of ROS in both cell lines and inhibited cell proliferation, migration, and colony formation. Oxidative stress induced by pimozide caused changes in the expression of antioxidant enzymes (SOD1, peroxiredoxin 6, and glutathione peroxidase 2) and CISD2. Co-treatment with glutathione, an antioxidant, reduced pimozide-induced ROS levels, and counteracted the inhibition of cell proliferation. Administration of pimozide to TRAMP mice reduced the progression of prostate cancer with increased ROS generation and decreased SOD activity. These results suggest that the antipsychotic drug, pimozide, has beneficial effects in prostate cancer in vivo and in vitro. The mechanism of pimozide may be related to augmenting ROS generation. We recommend pimozide as a promising anticancer agent.

Keywords: TRAMP; drug repurposing; pimozide; prostate neoplasm; reactive oxygen species.