title: 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.affiliation: Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Department of Hematology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Cai
authors.affiliation: Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Guan-Zhong
authors.initials: GZ
authors.lastname: Chen
authors.affiliation: Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Chang-Chang
authors.initials: CC
authors.lastname: Jia
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Dong-Bo
authors.initials: DB
authors.lastname: Qiu
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Cong
authors.initials: C
authors.lastname: Du
authors.affiliation: Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Hematology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.affiliation: Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.|Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010868:Pimozide / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D050796:STAT3 Transcription Factor; D010868:Pimozide
keywords: STAT3 inhibitor; STAT3 signaling; hepatic cancer stem-like cells; pimozide; self-renewal