The ubiquitin-proteasome system is responsible for the regulation of cellular protein homeostasis. By inhibiting proteasome activity, the anti-proliferative signals and the apoptotic pathways can be activated in cells, which makes proteasome an attractive therapeutic target in cancer treatment. Ixazomib Citrate is the citrate form of Ixazomib. Ixazomib is an N-capped dipeptidyl leucine boronic acid that inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nmol/l (Ki value of 0.93 nmol/l). It also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites with IC50 values of 31 and 3500 nmol/l, respectively. The proteasome dissociation half-life (t1/2) for ixazomib is 18 minutes. In MDA-MB-231 cells expressing a 4 Ub-Luc reporter, ixazomib inhibited proteasome activity with an EC50 value of 525 nmol/l. In HEK293 cells stably expressing a NF-κB-Luc reporter, ixazomib inhibited TNF-α-induced activation of NF-κB pathway with an EC50 value of 55 nmol/l. The anti-proliferative effects of ixazomib in A375 (lung), H460 (lung), HCT-116 (colon), and HT-29 (colon) cells were determined by cell viability assay with LD50 values ranged from 19 – 58 nmol/l. In mice i.v. administrated with a single dose of ixazomib at 14 mg/kg, the blood volume distribution at steady state was 20.2 L/kg. In Sprague-Dawley rats i.v. injected with a single of ixazomib at 0.2 or 0.3 mg/kg, the plasma exposure (AUC0-48h) of ixazomib was 704 and 1070 h.ng/ml, respectively. In CB17-SCID mice bearing xenograft tumors, the maximum level of blood proteasome inhibition was 83.1% following an acute i.v. treatment of 14 mg/kg ixazomib. The tumor to blood AUE ratio for ixazomib in human prostate tumor (CWR22) and human lymphoma tumor (WSU-DLCL2s) xenografts was 1.56 and 2.03, respectively. Ixazomib dosed at 7 mg/kg or 14 mg/kg showed significant antitumor effects in xenografts 22 days after the administration.
Ixazomib citrate/枸橼酸艾沙佐米 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U266
13.66 µM
48 h
Inhibited cell proliferation
Molecules. 2023 Aug 30;28(17):6343.
MM.1S
1, 2, 4 µM
48 h
Induced cell apoptosis and cell cycle arrest
Molecules. 2023 Aug 30;28(17):6343.
HCC PDXOs
0.1 μM
48 h
To assess the effect of Ixazomib on the viability of HCC PDXOs, results showed that Ixazomib significantly reduced cell viability.
J Exp Clin Cancer Res. 2022 Aug 15;41(1):249.
HCC PDXOs
1 μM
48 h
To evaluate the cytotoxic effect of Ixazomib on HCC PDXOs, results showed that Ixazomib significantly reduced cell viability.
J Exp Clin Cancer Res. 2022 Aug 15;41(1):249.
L428
25 nM
24 h
Global transcriptome analyses of L428 cells treated with ixazomib showed significant gene changes with a 1.2 fold-change for 423 genes
Cancer Res. 2016 Jun 1;76(11):3319-31.
L540
25 nM
24 h
Global transcriptome analyses of L540 cells treated with ixazomib showed significant gene changes with a 1.2 fold-change for 4765 genes
Cancer Res. 2016 Jun 1;76(11):3319-31.
Jurkat
25 nM
24 h
Global transcriptome analyses of Jurkat cells treated with ixazomib showed significant gene changes with a 1.2 fold-change for 508 genes
Cancer Res. 2016 Jun 1;76(11):3319-31.
Ixazomib citrate/枸橼酸艾沙佐米 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
HCC PDX model
Oral gavage
7 mg/kg
Three times a week, continuous treatment
To evaluate the tumor inhibitory effect of Ixazomib in combination with Dinaciclib on HCC PDX models, results showed that the combination treatment significantly inhibited tumor growth.
J Exp Clin Cancer Res. 2022 Aug 15;41(1):249.
Mice
Multiple myeloma xenograft models
Orally
3 mg/kg
Twice weekly
The antitumor efficacy of M3258, bortezomib, and ixazomib was compared in vivo. In the U266B1 multiple myeloma model, ixazomib induced prolonged complete tumor regression.
Mol Cancer Ther. 2021 Aug;20(8):1378-1387
Mice
HF/HC/BS diet model
Oral
20 mg/kg
Single dose, 6 hours
To evaluate the effect of ixazomib on LXRα ubiquitination, results showed that ixazomib treatment significantly reduced the ubiquitination level of LXRα.
Nature. 2016 Jul 14;535(7611):303-7
Mice
IL6Myc mouse model
Intravenous injection
7 mg/kg
Twice weekly for 24 weeks
To evaluate the therapeutic response of ixazomib in IL6Myc mouse model of plasma cell tumors, results showed that ixazomib significantly extended the survival of mice.
Blood Cancer J. 2013 Nov 29;3(11):e165
SCID mice
Human lymphoma xenograft models derived from Jurkat and L540 cell lines
Intraperitoneal injection
0.36 mg/kg or 0.72 mg/kg
Daily for three weeks
Investigation of the antitumor activity of ixazomib in Jurkat and L540 xenograft models showed significant tumor growth inhibition and improved survival in mice
Cancer Res. 2016 Jun 1;76(11):3319-31.
NOD.SCID/NCR mice
A549 xenograft tumor model
Subcutaneous injection
15 mg/kg
Daily for 3 weeks
To evaluate the inhibitory effect of Ixazomib combined with AKT and SRC inhibitors on the growth of A549 xenograft tumors. The results showed that Ixazomib combined with MK-2206 or Saracatinib significantly reduced tumor growth, and the effect was greatest with the three-drug combination.
Nat Commun. 2021 Dec 3;12(1):6941.
Mice
H22 pulmonary metastasis tumor model
Oral
0.008 mmol/kg
Twice weekly for 2 weeks
Evaluated anti-metastasis efficacy, significantly reduced the number of pulmonary metastasis nodes
Molecules. 2023 Aug 30;28(17):6343.
Mice
AML xenograft model
Oral
8 mg/kg
Twice a week for 3 weeks
Ixazomib significantly inhibits tumor growth and is associated with suppression of FOXM1.
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