| 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 |
Related Documents
:
|
16378719 - The spitzenkörper: a molecular perspective. 21068059 - Non-cell-autonomously coordinated organ size regulation in leaf development. 11082279 - Shape-dependent control of cell growth, differentiation, and apoptosis: switching betwe... 18685789 - Proteome identification of binding-partners interacting with cell polarity protein par3... 20080649 - Dual function of ctla-4 in regulatory t cells and conventional t cells to prevent multi... 22282469 - Nucleolar sik-similar protein (sik-sp) is required for the maintenance of uterine estro... 9264249 - Epithelial differentiation in drosophila. 12359339 - Characterization of human stellate cell activation-associated protein and its expressio... 1333109 - Signet ring cell carcinoma of the stomach: a morphometric, ultrastructural, and dna cyt... |
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; |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Darbepoietin-? has comparable erythropoietic stimulatory effects to recombinant erythropoietin whils...
Next Document: Differential effects of rapamycin and retinoic acid on expansion, stability and suppressive qualitie...