dc.contributor.author | Starheim, Kristian Kobbenes | |
dc.contributor.author | Holien, Toril | |
dc.contributor.author | Misund, Kristine | |
dc.contributor.author | Johansson, Ida | |
dc.contributor.author | Baranowska, Katarzyna Anna | |
dc.contributor.author | Sponaas, Anne Marit | |
dc.contributor.author | Hella, Hanne | |
dc.contributor.author | Buene, Glenn | |
dc.contributor.author | Waage, Anders | |
dc.contributor.author | Sundan, Anders | |
dc.contributor.author | Bjørkøy, Geir | |
dc.date.accessioned | 2018-01-03T08:41:43Z | |
dc.date.available | 2018-01-03T08:41:43Z | |
dc.date.created | 2016-11-03T10:21:33Z | |
dc.date.issued | 2016 | |
dc.identifier.citation | Blood Cancer Journal. 2016, 6, e446. | nb_NO |
dc.identifier.issn | 2044-5385 | |
dc.identifier.uri | http://hdl.handle.net/11250/2474209 | |
dc.description.abstract | Multiple myeloma (myeloma in short) is an incurable cancer of antibody-producing plasma cells that comprise 13% of all hematological malignancies. The proteasome inhibitor bortezomib has improved treatment significantly, but inherent and acquired resistance to the drug remains a problem. We here show that bortezomib-induced cytotoxicity was completely dampened when cells were supplemented with cysteine or its derivative, glutathione (GSH) in ANBL-6 and INA-6 myeloma cell lines. GSH is a major component of the antioxidative defense in eukaryotic cells. Increasing intracellular GSH levels fully abolished bortezomib-induced cytotoxicity and transcriptional changes. Elevated intracellular GSH levels blocked bortezomib-induced nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2)-associated stress responses, including upregulation of the xCT subunit of the Xc- cystine-glutamate antiporter. INA-6 cells conditioned to increasing bortezomib doses displayed reduced bortezomib sensitivity and elevated xCT levels. Inhibiting Xc- activity potentiated bortezomib-induced cytotoxicity in myeloma cell lines and primary cells, and re-established sensitivity to bortezomib in bortezomib-conditioned cells. We propose that intracellular GSH level is the main determinant of bortezomib-induced cytotoxicity in a subset of myeloma cells, and that combined targeting of the proteasome and the Xc- cystine-glutamate antiporter can circumvent bortezomib resistance. | nb_NO |
dc.language.iso | eng | nb_NO |
dc.publisher | Nature Publishing Group | nb_NO |
dc.rights | Navngivelse 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/deed.no | * |
dc.title | Intracellular glutathione determines bortezomib cytotoxicity in multiple myeloma cells | nb_NO |
dc.type | Journal article | nb_NO |
dc.type | Peer reviewed | nb_NO |
dc.description.version | publishedVersion | nb_NO |
dc.source.volume | 6 | nb_NO |
dc.source.journal | Blood Cancer Journal | nb_NO |
dc.identifier.doi | 10.1038/bcj.2016.56 | |
dc.identifier.cristin | 1396890 | |
dc.relation.project | Kreftforeningen: 6799133 | nb_NO |
dc.relation.project | Kreftforeningen: 2215992 | nb_NO |
dc.relation.project | Norges forskningsråd: 223255 | nb_NO |
dc.description.localcode | © The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. | nb_NO |
cristin.unitcode | 194,65,15,0 | |
cristin.unitcode | 194,66,40,0 | |
cristin.unitname | Institutt for klinisk og molekylær medisin | |
cristin.unitname | Institutt for bioingeniørfag | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |