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

Authors
Seung Un SeoHyuk Ki ChoKyoung-jin MinSeon Min WooShin KimJong-Wook ParkSang Hyun KimYung Hyun ChoiYoung Sam KeumJin Won HyunHyun Ho ParkSang-Han LeeDong Eun KimTaeg Kyu Kwon
Department
Dept. of Immunology (면역학); Dept. of Otorhinolaryngology (이비인후과학)
Issue Date
2017
Citation
Cell Death & Disease, Vol.8(2) : e2599-e2599, 2017
ISSN
2041-4889
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.
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/32384
Appears in Collections:
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학)
Keimyung Author(s)
박종욱; 김동은; 권택규; 김신
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