Trifluoperazine as an alternative strategy for the inhibition of tumor growth of colorectal cancer

Abstract

The development of cancer in patients with schizophrenia is affected by genetic and environmental factors and antipsychotic medication. Several studies found that schizophrenia was associated with decreased risk of some cancers, and the neuroleptic medication might help to reduce the risk of colorectal cancer (CRC). Phenothiazine drugs including trifluoperazine (TFP) are widely used antipsychotic drugs and showed some antitumor effects, we here investigated the potential application of TFP in the treatment of colon cancer. A series doses of TFP were treated to the colon cancer cell line HCT116 and the inhibitory concentration (IC50) of TFP for HCT116 was determined by cell counting kit‐8. The results indicated that the treatment of TFP impaired the cell vitality of HCT116 in a dose‐ and time‐dependent manner. Meanwhile, the Edu assay demonstrated that the proliferation was also inhibited by TFP, which was accompanied with the induction of apoptosis and autophagy. The expression of CCNE1, CDK4, and antiapoptosis factor BCL‐2 was downregulated but the proapoptosis factor BAX was upregulated. The autophagy inhibitor chloroquine could significantly reverse the TFP‐induced apoptosis. Moreover, the ability of migration and invasion of HCT116 was found to be suppressed by TFP, which was associated with the inhibition of epithelial‐mesenchymal transition (EMT). The function of TFP in vivo was further confirmed. The results showed that the administration of TFP remarkably abrogated the tumor growth with decreased tumor volume and proliferation index Ki‐67 level in tumor tissues. The EMT phenotype was also confirmed to be inhibited by TFP in vivo, suggesting the promising antitumor effects of TFP in CRC.

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

“…Trifluoperazine also inhibited the migration and invasion capacity of a human colon carcinoma cell line as assayed in vitro. Most interestingly, this CaM antagonist also inhibited EMT in vivo as evidenced by the decreased expression of the EMT markers N-cadherin and the transcription factors Snail and Slug, increasing on the other hand the level of E-cadherin in the tumor cells [80].…”

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

“…For this reason, we have focused our attention on the TFP drug. Previously, we have rationally repurposed TFP [8], an antipsychotic drug, for treating PDAC, and others have demonstrated its anticancer activity in other cancers [4,14,15]. Nevertheless, the mechanisms of action by which TFP induces cell death are poorly understood.…”

“…In this regard, trifluoperazine (TFP) is a well-known member of the phenothiazine class of antipsychotic drugs. TFP has shown in vivo anticancer activity in glioblastoma [3], colorectal cancer [4], and triple-negative breast cancer [5], among others. Subsequently, several studies have demonstrated that TFP can inhibit cell migration and proliferation, promote cell cycle arrest, induce apoptosis, and inhibit autophagy in multiple cancer cell lines [6,7].…”

Trifluoperazine induces cellular apoptosis by inhibiting autophagy and targeting NUPR1 in multiple myeloma

“…Considering that TFP plays an inhibitory role in various tumors [5,15], we treated MM cells with different concentrations of TFP (0, 5, 10, 20, 30, 40 lm) to investigate the role of TFP in MM. After treatment for 24 h, we performed the CCK-8 assay to evaluate the cell viability.…”

“…Trifluoperazine (TFP) is a dopamine D2 receptor inhibitor and a phenothiazine derivative that has been used for many years as an antipsychotic drug [3]. TFP treatment impairs cell viability and induces mitochondria-mediated intrinsic apoptosis and autophagy [4][5][6]. It has thus been employed as an alternative therapeutic strategy for colorectal cancer, glioblastoma, and urothelial carcinoma.…”