Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties

Background: Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examin...

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Authors: Yip, N. C., Fombon, I. S., Liu, P., Brown, S., Kannappan, V., Armesilla, Angel L., Xu, Bing, Cassidy, J., Darling, J. L., Wang, Weiguang
Format: article
Publication Date:2011
Country:España
Institution:Universidad Camilo José Cela (UCJC)
Repository:Depósito Digital e-UCJC
OAI Identifier:oai:repositorio.ucjc.edu:20.500.12020/1562
Online Access:http://hdl.handle.net/20.500.12020/1562
https://doi.org/10.1038/bjc.2011.126
Access Level:Open access
Keyword:Ciencias Biomédicas
Disulfiram
NFkB
MAPK pathway
Reactive Oxygen Species
Breast Cancer Stem Cells
Paclitaxel
32 Ciencias Médicas
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spelling Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like propertiesYip, N. C.Fombon, I. S.Liu, P.Brown, S.Kannappan, V.Armesilla, Angel L.Xu, BingCassidy, J.Darling, J. L.Wang, WeiguangCiencias BiomédicasDisulfiramNFkBMAPK pathwayReactive Oxygen SpeciesBreast Cancer Stem CellsPaclitaxel32 Ciencias MédicasBackground: Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs). Methods: The effect of DS on BC cell lines and BCSCs was determined by MTT, western blot, CSCs culture and CSCs marker analysis. Results: Disulfiram was highly toxic to BC cell lines in vitro in a copper (Cu)-dependent manner. In Cu-containing medium (1 μM), the IC(50) concentrations of DS in BC cell lines were 200-500 nM. Disulfiram/copper significantly enhanced (3.7-15.5-fold) cytotoxicity of paclitaxel (PAC). Combination index isobologram analysis demonstrated a synergistic effect between DS/Cu and PAC. The increased Bax and Bcl2 protein expression ratio indicated that intrinsic apoptotic pathway may be involved in DS/Cu-induced apoptosis. Clonogenic assay showed DS/Cu-inhibited clonogenicity of BC cells. Mammosphere formation and the ALDH1(+VE) and CD24(Low)/CD44(High) CSCs population in mammospheres were significantly inhibited by exposure to DS/Cu for 24 h. Disulfiram/copper induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways. Meanwhile, the constitutive NFκB activity in BC cell lines was inhibited by DS/Cu. Conclusion: Disulfiram/copper inhibited BCSCs and enhanced cytotoxicity of PAC in BC cell lines. This may be caused by simultaneous induction of ROS and inhibition of NFκB.Springer Nature2011info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12020/1562https://doi.org/10.1038/bjc.2011.126reponame:Depósito Digital e-UCJCinstname:Universidad Camilo José Cela (UCJC)Inglésinfo:eu-repo/semantics/openAccessoai:repositorio.ucjc.edu:20.500.12020/15622026-05-27T07:36:51Z
dc.title.none.fl_str_mv Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
title Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
spellingShingle Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
Yip, N. C.
Ciencias Biomédicas
Disulfiram
NFkB
MAPK pathway
Reactive Oxygen Species
Breast Cancer Stem Cells
Paclitaxel
32 Ciencias Médicas
title_short Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
title_full Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
title_fullStr Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
title_full_unstemmed Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
title_sort Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties
dc.creator.none.fl_str_mv Yip, N. C.
Fombon, I. S.
Liu, P.
Brown, S.
Kannappan, V.
Armesilla, Angel L.
Xu, Bing
Cassidy, J.
Darling, J. L.
Wang, Weiguang
author Yip, N. C.
author_facet Yip, N. C.
Fombon, I. S.
Liu, P.
Brown, S.
Kannappan, V.
Armesilla, Angel L.
Xu, Bing
Cassidy, J.
Darling, J. L.
Wang, Weiguang
author_role author
author2 Fombon, I. S.
Liu, P.
Brown, S.
Kannappan, V.
Armesilla, Angel L.
Xu, Bing
Cassidy, J.
Darling, J. L.
Wang, Weiguang
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Biomédicas
Disulfiram
NFkB
MAPK pathway
Reactive Oxygen Species
Breast Cancer Stem Cells
Paclitaxel
32 Ciencias Médicas
topic Ciencias Biomédicas
Disulfiram
NFkB
MAPK pathway
Reactive Oxygen Species
Breast Cancer Stem Cells
Paclitaxel
32 Ciencias Médicas
description Background: Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs). Methods: The effect of DS on BC cell lines and BCSCs was determined by MTT, western blot, CSCs culture and CSCs marker analysis. Results: Disulfiram was highly toxic to BC cell lines in vitro in a copper (Cu)-dependent manner. In Cu-containing medium (1 μM), the IC(50) concentrations of DS in BC cell lines were 200-500 nM. Disulfiram/copper significantly enhanced (3.7-15.5-fold) cytotoxicity of paclitaxel (PAC). Combination index isobologram analysis demonstrated a synergistic effect between DS/Cu and PAC. The increased Bax and Bcl2 protein expression ratio indicated that intrinsic apoptotic pathway may be involved in DS/Cu-induced apoptosis. Clonogenic assay showed DS/Cu-inhibited clonogenicity of BC cells. Mammosphere formation and the ALDH1(+VE) and CD24(Low)/CD44(High) CSCs population in mammospheres were significantly inhibited by exposure to DS/Cu for 24 h. Disulfiram/copper induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways. Meanwhile, the constitutive NFκB activity in BC cell lines was inhibited by DS/Cu. Conclusion: Disulfiram/copper inhibited BCSCs and enhanced cytotoxicity of PAC in BC cell lines. This may be caused by simultaneous induction of ROS and inhibition of NFκB.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12020/1562
https://doi.org/10.1038/bjc.2011.126
url http://hdl.handle.net/20.500.12020/1562
https://doi.org/10.1038/bjc.2011.126
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:Depósito Digital e-UCJC
instname:Universidad Camilo José Cela (UCJC)
instname_str Universidad Camilo José Cela (UCJC)
reponame_str Depósito Digital e-UCJC
collection Depósito Digital e-UCJC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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