The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Osteosarcoma (OS) is an aggressive bone cancer with limited treatment options.
• STAT3 signaling activation correlates with poor prognosis in OS patients.
• Pimozide, an FDA-approved drug, has shown anti-tumor effects by inhibiting STAT3 in other cancers.

Purpose of the Study:

• To investigate the anti-cancer effects of pimozide on osteosarcoma cells.
• To elucidate the molecular mechanisms underlying pimozide's action in OS.
• To evaluate pimozide as a potential therapeutic agent for osteosarcoma.

Main Methods:

• Assessed pimozide's effects on OS cell proliferation, colony formation, and sphere formation.
• Analyzed cell cycle distribution and apoptosis markers (cleaved-PARP).
• Investigated pimozide's impact on cancer stem-like cells, Erk signaling, STAT3 activity, and reactive oxygen species (ROS) generation, including the role of catalase (CAT).

Main Results:

• Pimozide inhibited OS cell proliferation, colony formation, and sphere formation in a dose-dependent manner, inducing G0/G1 cell cycle arrest.
• Pimozide reduced cancer stem-like cells, enhanced sensitivity to 5-FU, and induced apoptosis.
• Pimozide suppressed Erk signaling, downregulated catalase (CAT) expression, increased ROS generation, and inhibited STAT3 activity, with NAC and CAT treatments partially reversing these effects.

Conclusions:

• Pimozide exhibits significant anti-osteosarcoma activity by inhibiting cell proliferation, stemness, and inducing apoptosis.
• Pimozide's mechanism involves STAT3 and Erk signaling suppression, leading to decreased catalase expression, increased ROS generation, and oxidative stress.
• Pimozide demonstrates potential as a novel therapeutic agent for osteosarcoma treatment, targeting STAT3 signaling.