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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-activated protein kinase (p38 MAPK) signaling pathways, and activation of 5′-AMP-dependent kinase (AMPK) signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS) generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2) in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy.

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Background: With the development of society, Neurodegenerative disease (ND), such as alzheimer's disease, is more and more important to the researchers. Metal iron may play a crucial role in this disease, so our research constructed the iron overloading model in nerve cells, induce the ferroptosis, simulate the state of the nerve in the body, and used the anesthesia Dexmedetomidine (Dex), and study whether the Dex can inhibit the ferroptosis and reduce the ND.Methods: Cell proliferation kit CCK8 and PI/Hoechst fluorescence double staining were used to detect the proliferation and apoptosis of HT22 cells. Western blot (WB) was used to detect the expression of PTGS2 and ACSL4, pathway proteins mTOR, TFR1. ROS content in HT22 cells was determined by DHE fluorescence probe. Lipid Peroxidation in nerve cells was detected by MDA Assay. Mito-ferrorange fluorescent probe was used to detect the level of ferrous ions in cells to demonstrate that ferroptosis occurred in nerve cells and Dex could protect nerve cells from ferroptosis.Results: Dex inhibits ferroptosis by regulating the mTOR-TFR1 pathway, reducing lipid peroxidation, intracellular reactive oxygen accumulation (ROS), reducing iron ions, and alleviating mitochondrial damage. mTOR is a well-known autophagy target and has been found to be closely related to ferroptosis. Dex activates the mTOR pathway, inhibits iron entry into the cell, reduces iron influx, and prevents ferroptosis by fenton reaction between excessive iron and lipids in the cell.Conclusion: Dex protects nerve cells from ferroptosis by regulating the mTOR-TFR1 pathway.