Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 192, Issue 4, Pages 747-760Publisher
WILEY
DOI: 10.1111/bjh.17284
Keywords
deferasirox; mantle cell lymphoma; cyclin D1; ROS; GSK3 beta
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The iron chelator deferasirox shows anti-tumor effects in MCL cells by inducing ROS, oxidative stress, and DNA damage to trigger CD1 proteolysis, while also mediating CD1 proteolysis by inhibiting the PI3K/AKT/GSK3 beta pathway. These findings suggest that deferasirox could be a potential therapeutic option for MCL patients.
Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by cyclin D1 (CD1) overexpression. Targeting CD1 in MCL has been shown to be of therapeutic significance. However, treatment of MCL remains challenging since patients are still subject to early and frequent relapse of the disease. To ensure their high proliferation rate, tumour cells have increased iron needs, making them more susceptible to iron deprivation. Indeed, several iron chelators proved to be effective anti-cancer agents. In this study, we demonstrate that the clinically approved iron chelator deferasirox (DFX) exerts an anti-tumoural effect in MCL cell lines and patient cells. The exposure of MCL cells to clinically feasible concentrations of DFX resulted in growth inhibition, cell cycle arrest and induction of apoptosis. We show that DFX unfolds its cytotoxic effect by a rapid induction of reactive oxygen species (ROS) that leads to oxidative stress and severe DNA damage and by triggering CD1 proteolysis in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase-3 beta (GSK3 beta). Moreover, we demonstrate that DFX mediates CD1 proteolysis by repressing the phosphatidylinositol 3-kinase (PI3K)/AKT/GSK3 beta pathway via ROS generation. Our data suggest DFX as a potential therapeutic option for MCL and paves the way for more treatment options for these patients.
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