title: Iron increases the susceptibility of multiple myeloma cells to bortezomib.
abstract: 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. 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. Multiple myeloma cell lines are characterized by distinct ferritin levels, which directly correlate with bortezomib resistance. We observed that iron supplementation upon bortezomib promotes protein oxidation and cell death, and that iron toxicity inversely correlates with basal ferritin levels. Bortezomib prevents ferritin upregulation in response to iron, thus limiting the ability to buffer reactive oxygen species. Consequently, 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. Bortezomib affects iron homeostasis, sensitizing cells to oxidative damage. Modulation of iron status is a strategy worth exploring to improve the efficacy of proteasome inhibition therapies.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Campanella
authors.forename: Paolo
authors.initials: P
authors.lastname: Santambrogio
authors.forename: Francesca
authors.initials: F
authors.lastname: Fontana
authors.forename: Michela
authors.initials: M
authors.lastname: Frenquelli
authors.forename: Simone
authors.initials: S
authors.lastname: Cenci
authors.forename: Magda
authors.initials: M
authors.lastname: Marcatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005293:Ferritins / Q000097:blood; D006801:Humans; D020128:Inhibitory Concentration 50; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D005293:Ferritins; D007501:Iron