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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.

Niu NK, Wang ZL, Pan ST, Ding HQ, Au GH, He ZX, Zhou ZW, Xiao G, Yang YX, Zhang X, Yang T, Chen XW, Qiu JX, Zhou SF - Drug Des Devel Ther (2015)

Bottom Line: 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 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.ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Spinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Department of Orthopedics, General Hospital of Tianjin Medical University, Tianjin, People's Republic of China.

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-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.

No MeSH data available.


Related in: MedlinePlus

(A) The chemical structure of ALS and (B) the cytotoxicity of ALS toward U-2 OS and MG-63 cells.Notes: The cytotoxic effects of ALS on U-2 OS and MG-63 were determined by the MTT assay. The cells were treated with ALS at 0.01 to 50 μM for 24 hours. Data are the mean ± SD of three independent experiments.Abbreviations: ALS, alisertib; MTT, thiazolyl blue tetrazolium bromide; SD, standard deviation; IC50, half maximal inhibitory concentration; OS, osteosarcoma.
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f1-dddt-9-1555: (A) The chemical structure of ALS and (B) the cytotoxicity of ALS toward U-2 OS and MG-63 cells.Notes: The cytotoxic effects of ALS on U-2 OS and MG-63 were determined by the MTT assay. The cells were treated with ALS at 0.01 to 50 μM for 24 hours. Data are the mean ± SD of three independent experiments.Abbreviations: ALS, alisertib; MTT, thiazolyl blue tetrazolium bromide; SD, standard deviation; IC50, half maximal inhibitory concentration; OS, osteosarcoma.

Mentions: Alisertib (ALS; also called MLN8237) (Figure 1A) is a small molecule inhibitor of AURKA that plays a pivotal role in centrosome maturation and spindle formation during mitosis.23 Inhibition of AURKA leads to mitotic errors, followed by aneuploidy, apoptosis, and senescence.18 In vitro studies by our laboratory have shown that ALS induces cancer cell apoptosis and autophagy and inhibits epithelial to mesenchymal transition (EMT) via activation of mitochondrial pathway, up-regulation of p53, and inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling pathway in breast, pancreatic, ovarian, and gastric cancer.24,25 However, the role of ALS in the treatment of OS is unclear.


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.

Niu NK, Wang ZL, Pan ST, Ding HQ, Au GH, He ZX, Zhou ZW, Xiao G, Yang YX, Zhang X, Yang T, Chen XW, Qiu JX, Zhou SF - Drug Des Devel Ther (2015)

(A) The chemical structure of ALS and (B) the cytotoxicity of ALS toward U-2 OS and MG-63 cells.Notes: The cytotoxic effects of ALS on U-2 OS and MG-63 were determined by the MTT assay. The cells were treated with ALS at 0.01 to 50 μM for 24 hours. Data are the mean ± SD of three independent experiments.Abbreviations: ALS, alisertib; MTT, thiazolyl blue tetrazolium bromide; SD, standard deviation; IC50, half maximal inhibitory concentration; OS, osteosarcoma.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362906&req=5

f1-dddt-9-1555: (A) The chemical structure of ALS and (B) the cytotoxicity of ALS toward U-2 OS and MG-63 cells.Notes: The cytotoxic effects of ALS on U-2 OS and MG-63 were determined by the MTT assay. The cells were treated with ALS at 0.01 to 50 μM for 24 hours. Data are the mean ± SD of three independent experiments.Abbreviations: ALS, alisertib; MTT, thiazolyl blue tetrazolium bromide; SD, standard deviation; IC50, half maximal inhibitory concentration; OS, osteosarcoma.
Mentions: Alisertib (ALS; also called MLN8237) (Figure 1A) is a small molecule inhibitor of AURKA that plays a pivotal role in centrosome maturation and spindle formation during mitosis.23 Inhibition of AURKA leads to mitotic errors, followed by aneuploidy, apoptosis, and senescence.18 In vitro studies by our laboratory have shown that ALS induces cancer cell apoptosis and autophagy and inhibits epithelial to mesenchymal transition (EMT) via activation of mitochondrial pathway, up-regulation of p53, and inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling pathway in breast, pancreatic, ovarian, and gastric cancer.24,25 However, the role of ALS in the treatment of OS is unclear.

Bottom Line: 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 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.ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Spinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Department of Orthopedics, General Hospital of Tianjin Medical University, Tianjin, People's Republic of China.

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-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.

No MeSH data available.


Related in: MedlinePlus