Document Detail


Iron increases the susceptibility of multiple myeloma cells to bortezomib.
MedLine Citation:
PMID:  23242599     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background Multiple myeloma is a malignant still incurable plasma cell disorder. Pharmacological treatment based on proteasome inhibition has improved patient outcome, however bortezomib-resistance remains a major clinical problem. Inhibition of proteasome functionality affects cellular iron homeostasis and iron is a potent inducer of reactive oxygen species and cell death, unless safely stored in ferritin. We explored the potential role of iron in bortezomib-resistance. Design and Methods We analyzed iron proteins, oxidative status and cell viability in 7 multiple myeloma cell lines and in plasma cells from 5 patients. Cells were treated with increasing bortezomib concentrations with or without iron supplementation. We reduced ferritin levels by both shRNA technology and by drug induced iron starvation. Results Multiple myeloma cell lines are characterized by distinct ferritin levels, which directly correlate with bortezomib resistance. We observed that iron supplementation upon bortezomib promotes proteins oxidation and cell death and that iron toxicity inversely correlates with basal ferritin levels. Bortezomib prevents ferritin up-regulation in response to iron, thus limiting the ability to buffer reactive oxygen species. In accordance, reduction of basal ferritin levels increases both bortezomib sensitivity and iron toxicity. In patients cells we confirmed that bortezomib prevents ferritin increase, that iron supplementation upon bortezomib increases cell death and that ferritin reduction overcomes bortezomib resistance. Conclusions Bortezomib affects iron homeostasis sensitizing cells to oxidative damage. Modulation of iron status is a strategy worth to be explored to improve the efficacy of proteasome inhibition therapies.
Authors:
Alessandro Campanella; Paolo Santambrogio; Francesca Fontana; Michela Frenquelli; Simone Cenci; Magda Marcatti; Roberto Sitia; Giovanni Tonon; Clara Camaschella
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-14
Journal Detail:
Title:  Haematologica     Volume:  -     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Milan, Italy;
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