1. Academic Validation
  2. The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression

The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression

  • Am J Transl Res. 2017 Aug 15;9(8):3853-3866.
Nan Cai 1 2 Wei Zhou 3 Lan-Lan Ye 1 Jun Chen 2 Qiu-Ni Liang 1 Gang Chang 1 Jia-Jie Chen 1
Affiliations

Affiliations

  • 1 School of Medicine, Shenzhen UniversityShenzhen 518060, People's Republic of China.
  • 2 College of Life Sciences and Oceanography, Shenzhen Key Laboratory of Marine Bioresources and Ecology, Shenzhen UniversityShenzhen 518060, People's Republic of China.
  • 3 Department of Spine Surgery and Joint Surgery, The Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510150, People's Republic of China.
PMID: 28861175
Abstract

Currently, there is a considerable need to develop new treatments for osteosarcoma (OS), a very aggressive bone Cancer. The activation of STAT3 signaling is positively associated with poor prognosis and aggressive progression in OS patients. Our previous study reported that the FDA-approved antipsychotic drug pimozide had anti-tumor activity against hepatocellular carcinoma and prostate Cancer cells by suppressing STAT3 activity. Therefore, the aim of this study was to investigate the specific effect of pimozide on OS cells and the underlying molecular mechanism. Pimozide inhibited cell proliferation, colony formation, and sphere formation capacities of the OS cells in a dose-dependent manner, inducing G0/G1 phase cell cycle arrest. Pimozide reduced the percentage of side population cells representing Cancer stem-like cells and enhanced the sensitivity of OS cells to 5-FU induced proliferative inhibition. In addition, pimozide induced Apoptosis of U2OS cells, which showed increased expression of cleaved-PARP, a marker of programmed cell death. Moreover, pimozide suppressed ERK signaling in OS cells. Importantly, pimozide induced ROS generation by downregulating the expression of the antioxidant Enzyme catalase (CAT). NAC treatment partially reversed the ROS generation and cytotoxic effects induced by pimozide. CAT treatment attenuated the pimozide-induced proliferation inhibition. The decrease of CAT expression induced by pimozide was potentially mediated through the suppression of cellular STAT3 activity in OS cells. Thus, pimozide may be a novel STAT3 Inhibitor that suppresses cellular STAT3 activity to inhibit OS cells or stem-like cells and is a novel potential anti-cancer agent in OS treatment.

Keywords

Pimozide; ROS; STAT3 inhibitor; osteosarcoma; translational medicine.

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