The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma.

Abstract

Drug repurposing is currently an important approach for accelerating drug discovery and development for clinical use. Hepatocellular carcinoma (HCC) presents drug resistance to chemotherapy, and the prognosis is poor due to the existence of liver cancer stem-like cells. In this study, we investigated the effect of the neuroleptic agent pimozide to inhibit stem-like cell maintenance and tumorigenicity in HCC. Our results showed that pimozide functioned as an anti-cancer drug in HCC cells or stem-like cells. Pimozide inhibited cell proliferation and sphere formation capacities in HCC cells by inducing G0/G1 phase cell cycle arrest, as well as inhibited HCC cell migration. Surprisingly, pimozide inhibited the maintenance and tumorigenicity of HCC stem-like cells, particularly the side population (SP) or CD133-positive cells, as evaluated by colony formation, sphere formation and transwell migration assays. Furthermore, pimozide was found to suppress STAT3 activity in HCC cells by attenuating STAT3-dependent luciferase activity and down-regulating the transcription levels of downstream genes of STAT3 signaling. Moreover, pimozide reversed the stem-like cell tumorigenic phenotypes induced by IL-6 treatment in HCC cells. Further, the antitumor effect of pimozide was also proved in the nude mice HCC xenograft model. In short, the anti-psychotic agent pimozide may act as a novel potential anti-tumor agent in treating advanced HCC.

• Authors: Jia-Jie Chen, Nan Cai, Guan-Zhong Chen, Chang-Chang Jia, Dong-Bo Qiu, Cong Du, Wei Liu, Yang Yang, Zi-Jie Long, Qi Zhang
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 11 Pg. 17593-17609 (Mar 14 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 26061710 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Antipsychotic Agents
• STAT3 Transcription Factor
• Pimozide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antipsychotic Agents (pharmacology)
• Blotting, Western
• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Liver Neoplasms (pathology)
• Male
• Mice
• Mice, Nude
• Neoplastic Stem Cells (drug effects)
• Pimozide (pharmacology)
• Real-Time Polymerase Chain Reaction
• STAT3 Transcription Factor (biosynthesis, drug effects)
• Transcriptome (drug effects)
• Xenograft Model Antitumor Assays