Oncotarget

Research Papers:

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

Jia-Jie Chen, Nan Cai, Guan-Zhong Chen, Chang-Chang Jia, Dong-Bo Qiu, Cong Du, Wei Liu, Yang Yang, Zi-Jie Long and Qi Zhang _

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Oncotarget. 2017; 8:17593-17609. https://doi.org/10.18632/oncotarget.4307

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Abstract

Jia-Jie Chen1,3,4,*, Nan Cai1,3,*, Guan-Zhong Chen1,2,*, Chang-Chang Jia1,3, Dong-Bo Qiu2,3, Cong Du2,3, Wei Liu1,2, Yang Yang1, Zi-Jie Long4 and Qi Zhang1,2,3

1 Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China

2 Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China

3 Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China

4 Department of Hematology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China

* These authors have contributed equally to this work

Correspondence to:

Qi Zhang, email:

Zi-Jie Long, email:

Keywords: pimozide, hepatic cancer stem-like cells, self-renewal, STAT3 signaling, STAT3 inhibitor

Received: February 11, 2015 Accepted: May 13, 2015 Published: May 27, 2015

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.


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