Pre-Clinical Evaluation of the Proteasome Inhibitor Ixazomib against Bortezomib-Resistant Leukemia Cells and Primary Acute Leukemia Cells

Margot S.F Roeten,Jacqueline Cloos,Wouter H Segerink,Johan Van Meerloo,Sonja Zweegman,Gertjan J.L Kaspers,Gerrit Jansen,Zinia J Kwidama,Giovanna Ter Huizen

doi:10.3390/cells10030665

Margot S.F Roeten, Jacqueline Cloos + Show 7 more

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https://doi.org/10.3390/cells10030665

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Abstract

At present, 20–30% of children with acute leukemia still relapse from current chemotherapy protocols, underscoring the unmet need for new treatment options, such as proteasome inhibition. Ixazomib (IXA) is an orally available proteasome inhibitor, with an improved safety profile compared to Bortezomib (BTZ). The mechanism of action (proteasome subunit inhibition, apoptosis induction) and growth inhibitory potential of IXA vs. BTZ were tested in vitro in human (BTZ-resistant) leukemia cell lines. Ex vivo activity of IXA vs. BTZ was analyzed in 15 acute lymphoblastic leukemia (ALL) and 9 acute myeloid leukemia (AML) primary pediatric patient samples. BTZ demonstrated more potent inhibitory effects on constitutive β5 and immunoproteasome β5i proteasome subunit activity; however, IXA more potently inhibited β1i subunit than BTZ (70% vs. 29% at 2.5 nM). In ALL/AML cell lines, IXA conveyed 50% growth inhibition at low nanomolar concentrations, but was ~10-fold less potent than BTZ. BTZ-resistant cells (150–160 fold) displayed similar (100-fold) cross-resistance to IXA. Finally, IXA and BTZ exhibited anti-leukemic effects for primary ex vivo ALL and AML cells; mean LC50 (nM) for IXA: 24 ± 11 and 30 ± 8, respectively, and mean LC50 for BTZ: 4.5 ± 1 and 11 ± 4, respectively. IXA has overlapping mechanisms of action with BTZ and showed anti-leukemic activity in primary leukemic cells, encouraging further pre-clinical in vivo evaluation.

Highlights

Acute leukemia is the most common type of pediatric malignancy, accounting for almost 30% of all cancer cases in this age group [1]
Building upon the successful application of the proteasome inhibitor (PI) Bortezomib (BTZ) in the treatment of multiple myeloma (MM) [7,8,9,10] and some solid tumors [11], BTZ has been proposed for the treatment of acute leukemia [12,13,14]
The inhibition profile by IXA vs. BTZ of two constitutive proteasome subunits β5 and β1 and their immunoproteasome counterparts β5i and β1i was examined in CEM

Summary

Introduction

Acute leukemia is the most common type of pediatric malignancy, accounting for almost 30% of all cancer cases in this age group [1]. BTZ has already been evaluated in pediatric acute leukemia, either alone or in combination with other common anti-leukemic drugs such as dexamethasone, vincristine, doxorubicin, and asparaginase. These clinical trials mainly involved relapsed ALL and showed promising results with complete remission rates up to 80%, without excessive toxicity, but recurrences occur [14,15,16,17,18,19]. For pediatric AML, a recent study revealed that BTZ in combination with standard chemotherapy did not improve treatment outcome [20] These observations, as well as the development of resistance to BTZ and the fact that peripheral neuropathy (PN)

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