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Antipsychotic Drug Trifluoperazine as a Potential Therapeutic Agent against Nasopharyngeal Carcinoma

ABSTRACT: Trifluoperazine (TFP), a typical antipsychotic primarily used for treating schizophrenia, exhibits anticancer effect on several types of cancer in recent years. Nevertheless, the effect of TFP on na-sopharyngeal carcinoma (NPC) is still unknown. In this study, we aimed to evaluate if TFP can be the potential therapeutic agent against NPC and to identify its underlying molecular mechanisms. We used four NPC cell lines, namely TW01, TW03, TW04, and BM, to assess the anticancer effects of TFP using cytotoxicity, wound healing, colony formation, and cell invasion assays. RNA se-quencing combined with Ingenuity Pathways Analysis was performed to identify the mechanism by which TFP influences NPC cells. Our data revealed that TFP decreased NPC cell viability in a dose-dependent manner. The invasion and migration of NPC cells were inhibited by TFP. RNA sequencing showed several anticancer molecular mechanisms after TFP administration. It is promising that the antipsychotic drug TFP can be used as a potential therapeutic regimen in NPC treatment in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192860 | GEO | 2023/12/21

REPOSITORIES: GEO

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Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways. comparison of olanzapine treated rats vs. control rats for genome-wide DNA methylation changes