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

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/486223.do
DOI
10.1038/cddis.2017.8
Title
Thioridazine enhances sensitivity to carboplatin in human head and neckcancer cells through downregulation of c-FLIP and Mcl-1 expression
Description
This work was supported by an NRF grant funded by the Korea Government(MSIP) (2014R1A5A2010008).
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.
provenance
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language
English
author
Seo, Seung Un
Cho, Hyuk Ki
Min, Kyoung-jin
Woo, Seon Min
Kim, Shin
Park, Jong-Wook
Kim, Sang Hyun
Choi, Yung Hyun
Keum, Young Sam
Hyun, Jin Won
Park, Hyun Ho
Lee, Sang-Han
Kim, Dong Eun
Kwon, Taeg Kyu
accessioned
2018-09-28T16:01:50Z
available
2018-09-28T16:01:50Z
issued
2017
citation
CELL DEATH & DISEASE(8)
issn
2041-4889
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/486223.do
Funder
교육부
Funding Program
BK21플러스사업(0.5)
Project ID
1345274240
Jurisdiction
Rep.of Korea
Project Name
Human Resource Development in the Field of Bio-Technological Application of Cellular Activity
rights
openAccess
type
article


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