Iron increases the susceptibility of multiple myeloma cells to bortezomib

Alessandro Campanella, Paolo Santambrogio, Francesca Fontana, Michela Frenquelli, Simone Cenci, Magda Marcatti, Roberto Sitia, Giovanni Tonon, Clara Camaschella

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)971-979
Number of pages9
JournalHaematologica
Volume98
Issue number6
DOIs
Publication statusPublished - 2013

Fingerprint

Multiple Myeloma
Iron
Ferritins
Proteasome Endopeptidase Complex
Cell Death
Plasma Cells
Bortezomib
Reactive Oxygen Species
Homeostasis
Cell Line
Starvation
Small Interfering RNA
Cell Survival
Buffers
Proteins
Up-Regulation
Pharmacology
Technology

ASJC Scopus subject areas

  • Hematology

Cite this

Iron increases the susceptibility of multiple myeloma cells to bortezomib. / Campanella, Alessandro; Santambrogio, Paolo; Fontana, Francesca; Frenquelli, Michela; Cenci, Simone; Marcatti, Magda; Sitia, Roberto; Tonon, Giovanni; Camaschella, Clara.

In: Haematologica, Vol. 98, No. 6, 2013, p. 971-979.

Research output: Contribution to journalArticle

@article{03613e7ba03840e08b00760554e99423,
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.",
author = "Alessandro Campanella and Paolo Santambrogio and Francesca Fontana and Michela Frenquelli and Simone Cenci and Magda Marcatti and Roberto Sitia and Giovanni Tonon and Clara Camaschella",
year = "2013",
doi = "10.3324/haematol.2012.074872",
language = "English",
volume = "98",
pages = "971--979",
journal = "Haematologica",
issn = "0390-6078",
publisher = "NLM (Medline)",
number = "6",

}

TY - JOUR

T1 - Iron increases the susceptibility of multiple myeloma cells to bortezomib

AU - Campanella, Alessandro

AU - Santambrogio, Paolo

AU - Fontana, Francesca

AU - Frenquelli, Michela

AU - Cenci, Simone

AU - Marcatti, Magda

AU - Sitia, Roberto

AU - Tonon, Giovanni

AU - Camaschella, Clara

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84878442520&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878442520&partnerID=8YFLogxK

U2 - 10.3324/haematol.2012.074872

DO - 10.3324/haematol.2012.074872

M3 - Article

C2 - 23242599

AN - SCOPUS:84878442520

VL - 98

SP - 971

EP - 979

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 6

ER -