Using the Iron Chelator Deferasirox to Overcome Drug Resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by the t(11,14) translocation, resulting in cyclin D1 (CD1) overexpression. In addition to CD1 overexpression, pathways such as the B-cell receptor, PI3K/AKT/ GSK3β, NFκB and Wnt have been reported to be deregulated in MCL. Despite advancements in MCL treatment, most patients still relapse. Although the introduction of ibrutinib to relapsed/refractory MCL significantly improved the outcome of MCL patients, ibrutinib resistance has become a clinical obstacle. MCL treatments are thus pursued by studying novel agents with a broad spectrum of targets or by rationally combining existing therapies aiming for synergistic antitumor activities. Deferasirox (DFX) is a clinically approved iron chelator with only few side effects. DFX has been reported to exert anti-tumoral and synergistic effects in several types of cancers by affecting a multitude of targets. We have previously shown that DFX exerts a vigorous anti-tumoral effect via growth inhibition and induction of apoptosis in MCL cells through ROS elevation, triggering of oxidative stress, induction of DNA damage, modulation of PI3K/AKT/GSK3β signaling and most importantly by elimination of CD1 expression. The capacity of DFX to affect a multitude of targets establishes a solid basis for a possible synergistic interaction with other drugs, such that may overcome drug resistance in MCL. In this study we focused on assessing the efficiency of DFX combined with the established therapeutic-agents etoposide, cytarabine and ibrutinib in MCL cell-lines. We found that DFX synergizes with etoposide, cytarabine and ibrutinib, prompting remarkable anti-tumoral effects in MCL cells with combination index (CI) values < 1. Interestingly, the DFX-drug combinations achieved synergism regardless of the innate sensitivity of the cell-lines to the treatment: ibrutinib-resistant cells restored their sensitivity to the drug when it was combined with DFX. In addition, we found that the sensitivity of MCL cells towards the drugs correlated with the drugs ability to induce CD1 degradation. In agreement, DFX co-treatment enhanced CD1 degradation, especially in resistant cells.