Thioridazine enhances sensitivity to carboplatin in human head and neck cancer cells through downregulation of c-FLIP and Mcl-1 expression.
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.
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Seung Un
SU
Seo
Department of Otolaryngology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Hyuk Ki
HK
Cho
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Kyoung-Jin
KJ
Min
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Seon Min
SM
Woo
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Shin
S
Kim
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Jong-Wook
JW
Park
Deaprtment of Pharmacology, School of Medicine, Kyungpook National University, Daegu, South Korea.
Sang Hyun
SH
Kim
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, South Korea.
Yung Hyun
YH
Choi
Department of Biochemistry, College of Pharmacy, Dongguk University, Goyang 10326, South Korea.
Young Sam
YS
Keum
School of Medicine, Jeju National University, Jeju 63243, South Korea.
Jin Won
JW
Hyun
School of Biotechnology and Graduate School of Biochemistry at Yeungnam University, Gyeongsan 38541, South Korea.
Hyun Ho
HH
Park
School of Food Science & Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea.
Sang-Han
SH
Lee
Department of Otolaryngology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Dong Eun
DE
Kim
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Taeg Kyu
TK
Kwon
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D016190:Carboplatin / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013881:Thioridazine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D016190:Carboplatin; D046988:Proteasome Endopeptidase Complex; D013881:Thioridazine