Thioridazine enhances sensitivity to carboplatin in human head and neck cancer cells through downregulation of c-FLIP and Mcl-1 expression.

Abstract

Carboplatin is a less toxic analog of cisplatin, but carboplatin also has side effects, including bone marrow suppression. Therefore, to improve the capacity of the anticancer activity of carboplatin, we investigated whether combined treatment with carboplatin and thioridazine, which has antipsychotic and anticancer activities, has a synergistic effect on apoptosis. Combined treatment with carboplatin and thioridazine markedly induced caspase-mediated apoptosis in head and neck squamous cell carcinoma (AMC-HN4) cells. Combined treatment with carboplatin and thioridazine induced downregulation of Mcl-1 and c-FLIP expression. Ectopic expression of Mcl-1 and c-FLIP inhibited carboplatin plus thioridazine-induced apoptosis. We found that augmentation of proteasome activity had a critical role in downregulation of Mcl-1 and c-FLIP expression at the post-translational level in carboplatin plus thioridazine-treated cells. Furthermore, carboplatin plus thioridazine induced upregulation of the expression of proteasome subunit alpha 5 (PSMA5) through mitochondrial reactive oxygen species (ROS)-dependent nuclear factor E2-related factor 2 (Nrf2) activation. In addition, combined treatment with carboplatin and thioridazine markedly induced apoptosis in human breast carcinoma (MDA-MB231) and glioma (U87MG) cells, but not in human normal mesangial cells and normal human umbilical vein cells (EA.hy926). Collectively, our study demonstrates that combined treatment with carboplatin and thioridazine induces apoptosis through proteasomal degradation of Mcl-1 and c-FLIP by upregulation of Nrf2-dependent PSMA5 expression.

• Authors: Seung Un Seo, Hyuk Ki Cho, Kyoung-Jin Min, Seon Min Woo, Shin Kim, Jong-Wook Park, Sang Hyun Kim, Yung Hyun Choi, Young Sam Keum, Jin Won Hyun, Hyun Ho Park, Sang-Han Lee, Dong Eun Kim, Taeg Kyu Kwon
• Journal: Cell death & disease (Cell Death Dis) Vol. 8 Issue 2 Pg. e2599 (02 09 2017) ISSN: 2041-4889 [Electronic] England
• PMID: 28182008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• NF-E2-Related Factor 2
• Reactive Oxygen Species
• Carboplatin
• Proteasome Endopeptidase Complex
• Thioridazine

Topics

• Breast Neoplasms (drug therapy, metabolism)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Carboplatin (pharmacology)
• Cell Line
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Glioma (drug therapy, metabolism)
• Head and Neck Neoplasms (drug therapy, metabolism)
• Human Umbilical Vein Endothelial Cells (drug effects)
• Humans
• Mitochondria (drug effects, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Reactive Oxygen Species (metabolism)
• Thioridazine (pharmacology)
• Up-Regulation (drug effects)