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

Chen,Xiaozhong; Luo,Xiaoquan; Cheng,Yuan

doi:10.3892/ijmm.2018.3885

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

Authors:
- Xiaozhong Chen
- Xiaoquan Luo
- Yuan Cheng
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Affiliations: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China, Department of Neurosurgery, Nanchong Central Hospital, Second Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
Published online on: September 18, 2018 https://doi.org/10.3892/ijmm.2018.3885
Pages: 3300-3308
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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