首页|Chlorpromazine, an antipsychotic agent, induces G2/M phase arrest and apoptosis via regulation of the PI3K/AKT/mTOR-mediated autophagy pathways in human oral cancer

Chlorpromazine, an antipsychotic agent, induces G2/M phase arrest and apoptosis via regulation of the PI3K/AKT/mTOR-mediated autophagy pathways in human oral cancer

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  • NSTL
  • Elsevier
Chlorpromazine (CPZ), an FDA-approved phenothiazine derivative used to treat schizophrenia and other psychiatric disorders, has been demonstrated to have potential anti-tumor effects. However, the potential effects of CPZ on human oral cancer cells and the underlying molecular mechanisms remain unknown. In this study, treatment of human oral cancer cells with CPZ inhibited their proliferation and induced G2/M phase arrest. Treatment with CPZ induced apoptosis through the extrinsic death receptor and the intrinsic mitochondrial pathways. In addition, the induction of autophagy was observed by the formation of autophagosomes, the expression of autophagy-related proteins and activation of the PI3K/Akt/mTOR/p70S6K pathway. The CPZ-induced cell death was reversed by the pan-caspase inhibitor Z-VAD-FMK, by the autophagy inhibitor 3-MA and by the knockdown of LC3B using a shRNA (shLC3B), suggesting that autophagy promoted CPZ-induced apoptosis. Finally, CPZ significantly suppressed tumor growth in both a zebrafish oral cancer xenotransplantation model and in a murine model of 4-nitroquinoline-1 -oxide (4NQO)-induced oral cancer. Overall, this evidence demonstrated that CPZ is a novel promising strategy for the treatment of oral cancer.

ChlorpromazineOral cancerAutophagyPI3KAktmTORp70S6K pathway

Jhou, An-Jie、Chang, Hao-Chiun、Hung, Chih-Chang、Lin, Han-Chen、Lee, Yi-Chen、Liu, Wang-Ta、Han, Kuang-Fen、Lai, Yu-Wei、Lin, Mei-Ying、Lee, Chien-Hsing

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Kaohsiung Med Univ, Coll Med, Grad Inst Med, Dept Pharmacol, Kaohsiung 80708, Taiwan

MacKay Mem Hosp, Dept Orthopaed, Taipei 10449, Taiwan

Kaohsiung Med Univ, Dept Biotechnol, Kaohsiung 80708, Taiwan

Kaohsiung Med Univ, Grad Inst Med, Kaohsiung Med Univ Hosp, Coll Med,Dept Anat,Sch Med, Kaohsiung

Min Hwei Jr Coll Hlth Care Management, Dept Nursing, Tainan 73658, Taiwan

Natl Yang Ming Univ, Taipei City Hosp, Dept Urol, Div Urol,Sch Med,Renai Branch, Taipei 11221

Kaohsiung Municipal Ci Jin Hosp, Community Hlth Promot Ctr, Kaohsiung 80708, Taiwan

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2021

10.1016/j.bcp.2020.114403

Biochemical Pharmacology

Biochemical Pharmacology

ISTP
ISSN：0006-2952
年,卷(期)：2021.184
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