Drug design, development and therapy, 2015-01, Vol.9 (default), p.1555-1584
2015
Details
- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Drug design, development and therapy, 2015-01, Vol.9 (default), p.1555-1584
- Ort / Verlag
- New Zealand: Dove Medical Press Limited
- Erscheinungsjahr
- 2015
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1177-8881eISSN: 1177-8881DOI: 10.2147/DDDT.S74197Titel-ID: cdi_doaj_primary_oai_doaj_org_article_384aff6baefd4027b78bfd08ab9eedc2
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Activation, Adolescents, AKT protein, ALS, AMP, Analysis, Anticancer properties, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacology, Apoptosis, Apoptosis - drug effects, Aurora kinase, Autophagy, Autophagy - drug effects, Azepines - chemistry, Azepines - pharmacology, Biocompatibility, Biotechnology, Bone cancer, Bone tumors, Cancer therapies, Cell adhesion & migration, Cell cycle, Cell Cycle - drug effects, Cell death, Cell Proliferation - drug effects, Cell Survival - drug effects, Cellular signal transduction, Chemotherapy, Children, Crosstalk, Cyclin B1, Development and progression, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Drug therapy, E-cadherin, EMT, Enzyme inhibitors, Gene expression, Genetic aspects, Health aspects, Hospitals, Humans, Inhibition, Inhibitors, Kinases, Laboratories, MAP kinase, MAP Kinase Signaling System - drug effects, Mesenchyme, Metabolism, Metastasis, Mitochondria, Mitochondria - drug effects, Mitochondria - metabolism, Mitogen-Activated Protein Kinases - antagonists & inhibitors, Mitogen-Activated Protein Kinases - metabolism, Molecular Structure, Mortality, N-Cadherin, Nuclear engineering, Nuclear safety, Original Research, Osteosarcoma, Oxidative stress, Phagocytosis, Phenotypes, Phosphatidylinositol 3-Kinases - antagonists & inhibitors, Phosphatidylinositol 3-Kinases - metabolism, PI3K/Akt/mTOR pathway, Protein Kinase Inhibitors - chemistry, Protein Kinase Inhibitors - pharmacology, Proteins, Proto-Oncogene Proteins c-akt - antagonists & inhibitors, Proto-Oncogene Proteins c-akt - metabolism, Pyrimidines - chemistry, Pyrimidines - pharmacology, Rapamycin, Reactive oxygen species, Reactive Oxygen Species - metabolism, Sarcoma, Signal transduction, Signaling, Stress response, Structure-Activity Relationship, Surgery, TOR protein, TOR Serine-Threonine Kinases - antagonists & inhibitors, TOR Serine-Threonine Kinases - metabolism, Trends, Tumor Cells, Cultured