Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies.

Jessica Bordini,Federica Morisi,Clara Camaschella,Paolo Ghia,Alessandro Campanella,Paolo Cascio,Fulvia Cerruti

doi:10.3390/cancers12040970

Abstract

Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies.

Highlights

Cancer cells rearrange iron trafficking proteins to promote iron uptake and retention, to favor proliferation [1,2]
We have recently demonstrated the efficacy of exploiting iron toxicity to affect cancer cells growth in models of multiple myeloma (MM), a disease in which malignant plasma cells accumulate in the bone marrow and secrete monoclonal immunoglobulin, generating bone disease, organ failure and anemia [8]
We found that the proteasome inhibitor bortezomib, a compound commonly used in the setting of MM patients, impairs the physiologic response to iron excess, i.e., transferrin receptor 1 (TFR1) degradation and ferritin increase, abolishing the cellular defensive response against iron exposure and maximizing the toxicity of supplemented iron [10]

Summary

Introduction

Cancer cells rearrange iron trafficking proteins to promote iron uptake and retention, to favor proliferation [1,2]. The opposite holds true, since excess iron is toxic, even for cancer cells, because it catalyzes oxidative stress. Cancers 2020, 12, 970 surface to favor iron export [5,6]. Notwithstanding this coordinated response, exposure to iron excess increases the cytosolic iron pool, oxidative stress, and consequent cell damage [7]. We have recently demonstrated the efficacy of exploiting iron toxicity to affect cancer cells growth in models of multiple myeloma (MM), a disease in which malignant plasma cells accumulate in the bone marrow and secrete monoclonal immunoglobulin, generating bone disease, organ failure and anemia [8]

Methods

Results

Discussion

Conclusion