Cell lines

HepG2 and Hep3B cells

Preparation Method

Treated HepG2 and Hep3B cells with various concentrations of alisertib (7-5000 nM) for 48 hours and concentration-survival curves were plotted.

Reaction Conditions

7-5000 nM; 48 hours

Applications

The results clearly showed that alisertib inhibited cell growth in a concentration-dependent manner and cotreated with alisertib significantly enhanced the cytotoxicity of lenvatinib.

Animal models

MCL SCID mouse xenograft model

Dosage form

10 mg/kg and 30 mg/kg; p.o.

Preparation Method

There were 6 cohorts of 12 mice: vehicle control, MLN8237 at 10 mg/kg and 30 mg/kg PO once a day for 3 weeks, docetaxol at 10 mg/kg IP once/week × 4, MLN8237 at 10 mg/kg or 30 mg/kg for 3 weeks + docetaxel 10 mg/kg once/week × 4. MLN8237 doses were chosen based on prior dose finding studies provided by Millennium Pharmaceuticals, while docetaxel dose was based on a clinically relevant dose in mouse xenograft tumor model.

Applications

Both combination treatments with docetaxel significantly increased survival over single agent treatments using MLN8237 (10 mg/kg and 30 mg/kg), and high MLN8237 + docetaxel combination treatment increased survival over single agent treatment with docetaxel.

Alisertib (MLN8237), as an investigational, orally available, selective aurora A kinase inhibitor, is usually used for the treatment of solid tumors and hematologic malignancies.^[1]

In vitro experiment it shown that treatment with 0.05 μM- 0.5 μM MLN8237 in the leukemia, medulloblastoma, and neuroblastoma cell lines inhibited their cell growth maximumly. However, with >1 μM approximately MLN8237, there was a paradoxical increase in apparent survival in all three lines, most pronounced for Daoy medulloblastoma cell line.^[2]In vitro, MLN8237 is effective against both Ewing sarcoma and neuroblastoma cell lines with IC50 of 32 nM and 37 nM, respectively.^[4]And alisertib has growth inhibition against U-2 OS cells and MG-63 cells with IC50 of 16.6 μM and 9.5 μM, respectively.^[5]In addition, MLN8237 has aggressive inhibition against B-NHL cell proliferation with an IC50 of 10-50 nM and induced apoptosis with a dose- and time-dependent manner.^[6]

In vivo, treatment with 30 mg/kg the combination of alisertib and lenvatinib intraperitoneally, every 3 days, for 4 consecutive weeks in BALB/c athymic nude mice, significantly enhanced the antiproliferative and proapoptotic activities, compared with single drugs alone.^[3]In vivo efficacy test it indicated that mice were treated with 30 mg/kg MLN8237 for 21 days orally markedly reduced tumor burden and increased overall survival.^[7]

References:

[1] Pusalkar S, et al. Biotransformation Pathways and Metabolite Profiles of Oral [14C]Alisertib (MLN8237), an Investigational Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors. Drug Metab Dispos. 2020 Mar;48(3):217-229.

[2] Muscal JA, et al. Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines. Invest New Drugs. 2013 Feb;31(1):39-45.

[3] Hao J, et al. Antitumor Effect of Lenvatinib Combined with Alisertib in Hepatocellular Carcinoma by Targeting the DNA Damage Pathway. Biomed Res Int. 2021 Jul 22;2021:6613439.

[4] Carol H, et al. Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer. Cancer Chemother Pharmacol. 2011 Nov;68(5):1291-304.

[5] Niu NK, et al. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. Drug Des Devel Ther. 2015 Mar 12;9:1555-84.

[6] Qi W, et al. Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. Biochem Pharmacol. 2011 Apr 1;81(7):881-90.

[7] Gorgün G, et al. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010 Jun 24;115(25):5202-13.