The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

Feng, Zongyun; Xia, Yong; Gao, Tiantao; Xu, Fuyan; Lei, Qian; Cheng, Peng; Yang, Yufei; Xue, Qiang; Hu, Xi; Wang, Qianqian; Wang, Ranran; Ran, Zhiqiang; Zeng, Zhaolin; Yang, Nan; Xie, Zixin; Yu, Luoting

doi:10.1038/s41419-018-1046-3

Cited by 64 publications

(49 citation statements)

References 59 publications

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“…In fact, TFP also interferes with the invasive growth of multiple human cell types derived from lung and breast cancer, hepatocellular carcinoma, or T‐cell lymphoma. TFP offers a limited cytotoxic profile and is therefore discussed as potential available drug in cancer therapy (Feng et al , ; Pulkoski‐Gross et al , ). In glioblastoma, TFP suppresses tumor cell proliferation and invasion in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

et al. 2020

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The MYC protein is a transcription factor with oncogenic potential controlling fundamental cellular processes such as cell proliferation, metabolism, differentiation, and apoptosis. The MYC gene is a major cancer driver, and elevated MYC protein levels are a hallmark of most human cancers. We have previously shown that the brain acid‐soluble protein 1 gene (BASP1) is specifically downregulated by the v‐myc oncogene and that ectopic BASP1 expression inhibits v‐myc‐induced cell transformation. The 11‐amino acid effector domain of the BASP1 protein interacts with the calcium sensor calmodulin (CaM) and is mainly responsible for this inhibitory function. We also reported recently that CaM interacts with all MYC variant proteins and that ectopic CaM increases the transactivation and transformation potential of the v‐Myc protein. Here, we show that the presence of excess BASP1 or of a synthetic BASP1 effector domain peptide leads to displacement of v‐Myc from CaM. The protein stability of v‐Myc is decreased in cells co‐expressing v‐Myc and BASP1, which may account for the inhibition of v‐Myc. Furthermore, suppression of v‐Myc‐triggered transcriptional activation and cell transformation is compensated by ectopic CaM, suggesting that BASP1‐mediated withdrawal of CaM from v‐Myc is a crucial event in the inhibition. In view of the tumor‐suppressive role of BASP1 which was recently also reported for human cancer, small compounds or peptides based on the BASP1 effector domain could be used in drug development strategies aimed at tumors with high MYC expression.

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Section: Discussionmentioning

confidence: 99%

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

et al. 2020

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“…The results demonstrated that the upregulation of miR-128 inhibited the expression of cyclin D1 and Rb. Cyclin D1 is a critical protein for the regulation of the G1 phase of the cell cycle, and Rb promotes the transition of cells from G1 to S phase (29). Therefore, these data indicate that a decrease in miR-128 expression under ZD conditions promotes the occurrence of esophageal cancer by regulating cyclin D1 and Rb expression.…”

Section: Discussionmentioning

confidence: 70%

Methylation‑associated silencing of miR‑128 promotes the development of esophageal cancer by targeting COX‑2 in areas with a high incidence of esophageal cancer

Jin

Guo

et al. 2018

Int J Oncol

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Esophageal cancer is one of the most common cancer types in the world, with a widely varying incidence between different regions. Zinc deficiency (ZD) is very common in high-risk areas for esophageal cancer. Dietary ZD is reported to be associated with esophageal squamous cell carcinoma (ESCC). In the current study, the effects of ZD on tumorigenesis and expression of inflammatory factors were investigated in mice. It was identified that a ZD diet advanced ESCC and increased the expression of cyclooxygenase-2 (COX-2) prior to the occurrence of ESCC in mice. ZD significantly enhanced DNA methyltransferase (DNMT) activity and increased the expression of DNMT1 and DNMT3B. Furthermore, the expression of miR-128 was downregulated by methylation, and COX-2, a direct target of miR-128, was upregulated with the reduction in miR-128. Upregulation of miR-128 inhibited the cell cycle, proliferation and metastasis, and the expression of COX-2, cyclin D1 and retinoblastoma protein (Rb). Furthermore, the relative expression level of miR-128 was negatively associated with COX-2 in ESCC tissues. Collectively, these findings indicate that methylation-associated silencing of miR-128 promotes the development of esophageal cancer through upregulation of the expression of cyclin D1 and Rb by targeting COX-2 in ZD regions with a high incidence of esophageal cancer. Methylation-associated silencing of miR-128 promotes the development of esophageal cancer by targeting COX-2 in areas with a high incidence of esophageal cancer

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“…However, another therapeutic potential of TFP has been reported. TFP suppressed the growth of tumor and brain metastasis by inducing G0/G1 cell cycle arrest of triple-negative breast cancer (TNBC) without causing detectable side effects in vivo [ 37 ]. TFP, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Repositioning of the antipsychotic drug TFP for sepsis treatment

Park

Lee

et al. 2019

J Mol Med

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Sepsis is a disease responsible for the death of almost all critical patients. Once infected by virus or bacteria, patients can die due to systemic inflammation within a short period of time. Cytokine storm plays an essential role in causing organ dysfunction and septic shock. Thus, inhibition of cytokine secretion is considered very important in sepsis therapy. In this study, we found that TFP, an antipsychotic drug mainly used to treat schizophrenia by suppressing dopamine secretion, inhibited cytokine release from activated immune cells both in vitro and in vivo. Trifluoperazine (TFP) decreased the levels of pro-inflammatory cytokines without altering their transcription level. In LPS-induced endotoxemia and cecal content injection (CCI) models, TFP intraperitoneal administration improved survival rate. Thus, TFP was considered to inhibit the secretion of proteins through a mechanism similar to that of W7, a calmodulin inhibitor. Finally, we confirmed that TFP treatment relieved organ damage by estimating the concentrations of aspartate transaminase (AST), alanine transaminase (ALT), and blood urea nitrogen (BUN) in the serum. Our findings were regarded as a new discovery of the function of TFP in treating sepsis patients. Key messages • TFP inhibits LPS-induced activation of DCs by suppressing pro-inflammatory cytokine. • Treatment of TFP increases survival of LPS-induced endotoxemia and CCI sepsis models. • TFP exerted a protective effect against tissue or organ damage in animal models. Electronic supplementary material The online version of this article (10.1007/s00109-019-01762-4) contains supplementary material, which is available to authorized users.

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The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

Cited by 64 publications

References 59 publications

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

Methylation‑associated silencing of miR‑128 promotes the development of esophageal cancer by targeting COX‑2 in areas with a high incidence of esophageal cancer

Repositioning of the antipsychotic drug TFP for sepsis treatment

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