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.