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 Design, Development and Therapy
Ning-Kui NiuShu-Feng Zhou

Abstract

Osteosarcoma (OS) is the most common malignant bone tumor occurring mostly in children and adolescents between 10 and 20 years of age with poor response to current therapeutics. Alisertib (ALS, MLN8237) is a selective Aurora kinase A inhibitor that displays anticancer effects on several types of cancer. However, the role of ALS in the treatment of OS remains unknown. This study aimed to investigate the effects of ALS on the cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-a...Continue Reading

Citations

Jan 6, 2016·International Journal of Molecular Sciences·Bao-Jun RenShu-Feng Zhou
Mar 5, 2016·Journal of Cancer Research and Clinical Oncology·Jonas Cicenas
Apr 9, 2016·International Journal of Molecular Sciences·Atik Badshah ShaikhGe Zhang
Mar 22, 2016·Clinical and Experimental Pharmacology & Physiology·Cameron T DurlacherShu-Feng Zhou
May 14, 2016·Journal of Agricultural and Food Chemistry·Chia-Chieh WuPin-Ju Chueh
Jul 16, 2020·Nutrition and Cancer·Jayasindu Mathiyazhagan, Gothandam Kodiveri Muthukaliannan
Feb 15, 2017·Scientific Reports·Chi-Hao TsaiJaw-Jou Kang
May 12, 2018·BioMed Research International·Yi LiZiming Dong
Aug 6, 2019·Journal of Medicinal Chemistry·Baowen QiJianyou Shi

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Methods Mentioned

BETA
flow cytometry
fluorescence microscopy
protein assay
electrophoresis

Software Mentioned

Image Lab

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