Cancer Center Amsterdam, Department of Hematology, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands.
Princess Maxima Center of Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
Cells. 2021 Mar 17;10(3):665. doi: 10.3390/cells10030665.
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 LC (nM) for IXA: 24 ± 11 and 30 ± 8, respectively, and mean LC 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.
目前，20-30%的急性白血病患儿仍会从当前的化疗方案中复发，这突显了对新治疗选择的需求，如蛋白酶体抑制。Ixazomib（IXA）是一种口服可用的蛋白酶体抑制剂，与硼替佐米（BTZ）相比，安全性更好。在体外，在人（BTZ 耐药）白血病细胞系中测试了 IXA 与 BTZ 的作用机制（蛋白酶体亚基抑制，细胞凋亡诱导）和生长抑制潜力。在 15 例急性淋巴细胞白血病（ALL）和 9 例急性髓系白血病（AML）儿科患者的原代样本中分析了 IXA 与 BTZ 的体外活性。BTZ 对组成性β5 和免疫蛋白酶体β5i 蛋白酶体亚基活性具有更强的抑制作用；然而，IXA 比 BTZ 更能抑制β1i 亚基（2.5 nM 时分别为 70%和 29%）。在 ALL/AML 细胞系中，IXA 在低纳摩尔浓度下即可达到 50%的生长抑制，但比 BTZ 弱约 10 倍。BTZ 耐药细胞（150-160 倍）对 IXA 表现出相似的（100 倍）交叉耐药性。最后，IXA 和 BTZ 对原代 ALL 和 AML 细胞表现出抗白血病作用；IXA 的平均 LC（nM）分别为 24±11 和 30±8，BTZ 的平均 LC 分别为 4.5±1 和 11±4。IXA 与 BTZ 具有重叠的作用机制，并在原代白血病细胞中显示出抗白血病活性，鼓励进一步进行临床前体内评估。
