Trifluoperazine prevents FOXO1 nuclear excretion and reverses doxorubicin-resistance in the SHG44/DOX drug-resistant glioma cell line

Abstract

As a tumor suppressor, Forkhead box O1 (FOXO1) is located in the nucleus where it regulates gene expression and inhibits tumor progression. However, the antitumor effects of FOXO1 are attenuated in several tumors due to its translocation from the nucleus to the cytoplasm. Trifluoperazine (TFP) is able to reverse tumor drug resistance by inhibiting multidrug resistance (MDR), however, the detailed molecular mechanisms by which this occurs remain to be fully elucidated. In the present study, the doxorubicin (DOX)-resistant SHG44/DOX glioma cell line was established. The results showed that TFP promoted DOX-induced cytotoxicity, cell cycle arrest and early apoptosis using a Cell Counting Kit-8 and flow cytometry. In vivo experiments also demonstrated that DOX combined with TFP reduced tumor volumes and proliferation indices, and led to higher protein levels of FOXO1. In addition, TFP inhibited the nuclear exclusion of FOXO1, contributing toward the downregulation of MDR genes and an increase in intracellular DOX concentrations by reverse transcription-quantitative polymerase chain reaction, western blot analysis, immunofluorescence and spectrophotometer analysis. Therefore, TFP may inhibit DOX resistance by stimulating FOXO1 nuclear translocation and suppressing MDF genes in SHG44/DOX cells, contributing to promising clinical prospects for tumor chemotherapy.

Trifluoperazine, an Antipsychotic Drug, Effectively Reduces Drug Resistance in Cisplatin-Resistant Urothelial Carcinoma Cells via Suppressing Bcl-xL: An In Vitro and In Vivo Study

“…Another study also showed that TFP upregulated the Bax/Bcl-2 ratio to promote apoptosis [21]. Consistent with these findings, we found TFP enhanced cisplatin-induced cytotoxicity and alleviated cisplatin resistance in cisplatin-resistant T24/R cells via suppression of Bcl-xL [18,19,20,21,22,23] with activation of DNA damage marker, phospho-histone H2A.X, and with concurrent downregulation of Bcl-xL.…”

“…Trifluoperazine (TFP), a phenothiazine derivative, has been commonly used as an antipsychotic drug. Previous studies demonstrated that TFP alone or combined with chemotherapy effectively induced tumor inhibition [13,14,15,16,17]; moreover, it could circumvent drug resistance in various cancers [18,19,20,21,22,23]. The mechanisms underlying the antitumor effect of TFP have been reported to be associated with anti-cancer stem cell properties by suppression of stemness-associated expression, such as CD133, c-Myc, β-catenin, and modulating apoptotic factors, including Bax, Bad, Bcl-2, and caspases or cell cycle arrest.…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…It prevents calmodulin–isocitrate dehydrogenase binding that is relevant for the survival and migration of glioblastoma multiforme cells [ 535 ]. Finally, trifluoperazine enhanced the effects of doxorubicin on glioma cell growth by increasing the expression of the nuclear tumor suppressor Forkhead box O1 and reducing the levels of multidrug resistance genes [ 536 ]. Another example of drug repositioning is represented by pimozide, which through its effect as an antagonist at D2R, D3R, and D4R, has been used to explore the potential anti-metastatic activity in murine melanoma [ 537 ].…”

The essential role of long non-coding RNA GAS5 in glioma: interaction with microRNAs, chemosensitivity and potential as a biomarker

“…These results suggested that variation of GAS5 occured during treatment with specific chemotherapy drugs, and was connected with chemosensitivity in glioma. Trifluoperazine (TFP) regulated FOXO1, increasing the amount of FOXO1 in the nucleus, and thus increasing the cytotoxicity of doxorubicin 41 . It had also been reported that a combination of EGFR and EGF activated the PI3K/Akt signaling pathway, induced FOXO1 nuclear exclusion, and promoted the metastasis of glioblastoma 42 .…”