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

Cells

Gerrit Jansen¹  Giovannater Huizen²  WouterH. Segerink²  Jacqueline Cloos²  Johanvan Meerloo²  ZiniaJ. Kwidama²  MargotS.F. Roeten²  Sonja Zweegman²  GertjanJ.L. Kaspers³ 

[1] Amsterdam Rheumatology and Immunology Center, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands;Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands;Princess Maxima Center of Pediatric Oncology, 3584 CS Utrecht, The Netherlands;

关键词: leukemia;    proteasome;    proteasome inhibitor;    ixazomib;    BTZ resistance;    drug resistance;   

DOI  :  10.3390/cells10030665

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown