PUBLICATION
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
- Authors
- Jhou, A.J., Chang, H.C., Hung, C.C., Lin, H.C., Lee, Y.C., Liu, W.T., Han, K.F., Lai, Y.W., Lin, M.Y., Lee, C.H.
- ID
- ZDB-PUB-210104-1
- Date
- 2020
- Source
- Biochemical pharmacology 184: 114403 (Journal)
- Registered Authors
- Keywords
- Akt, Chlorpromazine, oral cancer, autophagy, PI3K, mTOR, p70S6K pathway
- MeSH Terms
-
- Phosphatidylinositol 3-Kinases/metabolism
- Mice, Inbred BALB C
- Zebrafish
- Autophagy/drug effects*
- Autophagy/physiology
- Mouth Neoplasms/drug therapy*
- Mouth Neoplasms/metabolism
- Mouth Neoplasms/pathology
- Extracellular Vesicles/drug effects
- Extracellular Vesicles/physiology
- Chlorpromazine/pharmacology*
- G2 Phase/drug effects
- Proto-Oncogene Proteins c-akt/metabolism
- Cell Line, Tumor
- Animals
- Xenograft Model Antitumor Assays/methods
- TOR Serine-Threonine Kinases/metabolism
- Antipsychotic Agents/pharmacology
- Antineoplastic Agents/pharmacology
- Humans
- PubMed
- 33388284 Full text @ Biochem. Pharmacol.
Citation
Jhou, A.J., Chang, H.C., Hung, C.C., Lin, H.C., Lee, Y.C., Liu, W.T., Han, K.F., Lai, Y.W., Lin, M.Y., Lee, C.H. (2020) 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. Biochemical pharmacology. 184:114403.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping