Repurposed antipsychotic chlorpromazine inhibits colorectal cancer and pulmonary metastasis by inducing G2/M cell cycle arrest, apoptosis, and autophagy.
Cancer Chemother Pharmacol
; 89(3): 331-346, 2022 03.
Article
em En
| MEDLINE
| ID: mdl-35067737
ABSTRACT
PURPOSE:
Despite efforts in developing effective therapeutic strategies, colorectal cancer (CRC) remains one of the most prevalent and lethal neoplasms. Repurposing approved drugs is an alluring strategy for developing anticancer agents. Some antipsychotic drugs, including chlorpromazine (CPZ), possess anticancer activities. However, the pharmacological effects of CPZ on CRC have not been clearly established.METHODS:
MTT assay, flow cytometry, western blotting analysis, subcutaneous mice tumor, and tail-vein-injection established lung metastasis model were used to investigate the anticancer effects of CPZ on CRC and the underlying mechanism.RESULTS:
We found that CPZ effectively suppressed CRC by inducing G2/M cell cycle arrest and apoptosis. Cell cycle arrest was associated with decreased activities of the cdc2/cyclin B1 complex, including suppressed expression of cyclin B1, cdc2 and cdc25c, and elevated expression levels of phosphorylated cdc2 (Tyr15). Moreover, CPZ suppressed mitochondrial membrane potential and elevated reactive oxygen species levels in cancer cells, implying that it induces mitochondria-dependent intrinsic apoptosis. CPZ blocked the autophagic flux and induced cytotoxic autophagy in CRC cells. In addition, CPZ suppressed tumor growth in two subcutaneous mouse models without causing obvious side effects. Analysis of the abundance of immune cells in the tumor microenvironment revealed that CPZ did not have an effect on their proportions. Furthermore, it significantly suppressed the lung metastasis of CT26 cells and prolonged mice survival.CONCLUSION:
These findings indicated that repurposing CPZ is a novel treatment strategy for CRC patients.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antipsicóticos
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Neoplasias Colorretais
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Neoplasias Pulmonares
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article