Background
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]
参考文献:
[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] G?rgün 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.
Alisertib (MLN8237) 作为一种在研、可口服的选择性极光 A 激酶抑制剂，通常用于治疗实体瘤和血液系统恶性肿瘤。[1]
体外实验表明，在白血病、髓母细胞瘤和神经母细胞瘤细胞系中用 0.05 μM- 0.5 μM MLN8237 处理可最大程度地抑制它们的细胞生长。然而，在 >1 μM 大约 MLN8237 的情况下，所有三个细胞系的表观存活率都出现了矛盾的增加，对于 Daoy 髓母细胞瘤细胞系最为明显。[2]在体外，MLN8237 对尤文肉瘤和神经母细胞瘤细胞系的 IC50 分别为 32 nM 和 37 nM。[4] alisertib 对 U-2 OS 细胞和 MG-63 细胞具有生长抑制作用，IC50 为 16.6 μM 和 9.5 μM , 分别。[5] 此外，MLN8237 对 B-NHL 细胞增殖具有积极的抑制作用，IC50 为 10-50 nM，并以剂量和时间依赖的方式诱导细胞凋亡。 [6]
在体内，与单独使用单一药物相比，在 BALB/c 无胸腺裸鼠中连续 4 周每 3 天腹膜内注射 30 mg/kg alisertib 和乐伐替尼的组合，显着增强了抗增殖和促凋亡活性。 [3] 体内药效试验表明，小鼠口服 30 mg/kg MLN8237 21 天可显着降低肿瘤负荷并提高总生存期。[7] /p>
Protocol
| Cell experiment [1]: |
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Cell lines
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HepG2 and Hep3B cells
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Preparation Method
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Treated HepG2 and Hep3B cells with various concentrations of alisertib (7-5000 nM) for 48 hours and concentration-survival curves were plotted.
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Reaction Conditions
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7-5000 nM; 48 hours
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Applications
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The results clearly showed that alisertib inhibited cell growth in a concentration-dependent manner and cotreated with alisertib significantly enhanced the cytotoxicity of lenvatinib.
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| Animal experiment [2]: |
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Animal models
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MCL SCID mouse xenograft model
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Dosage form
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10 mg/kg and 30 mg/kg; p.o.
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Preparation Method
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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.
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Applications
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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.
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参考文献:
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.
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.
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