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Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells.

Ding,YH, Zhou,ZW, Ha,CF, Zhang,XY, Pan,ST, He,ZX, Edelman,JL, Wang,D, Yang,YX, Zhang,X, Duan,W, Yang,T, Qiu,JX and Zhou,SF 2015, Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells., Drug Design, Development and Therapy, vol. 9, pp. 425-464, doi: 10.2147/DDDT.S74062.

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Title Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells.
Author(s) Ding,YH
Zhou,ZW
Ha,CF
Zhang,XY
Pan,ST
He,ZX
Edelman,JL
Wang,D
Yang,YX
Zhang,X
Duan,WORCID iD for Duan,W orcid.org/0000-0001-5782-9184
Yang,T
Qiu,JX
Zhou,SF
Journal name Drug Design, Development and Therapy
Volume number 9
Start page 425
End page 464
Publisher Dove Medical Press
Place of publication New Zealand
Publication date 2015
ISSN 1177-8881
Keyword(s) Aurora kinase A
alisertib
apoptosis
autophagy
cell cycle
epithelial ovarian cancer
epithelial to mesenchymal transition
sirtuin 1
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
ADVANCED SOLID TUMORS
INVESTIGATIONAL AURORA
SELECTIVE AURORA
A KINASE
IN-VITRO
PHASE-I
PLATINUM-RESISTANT
PROSTATE-CANCER
LEUKEMIA-CELLS
CYTOCHROME-C
Summary Ovarian cancer is a leading killer of women, and no cure for advanced ovarian cancer is available. Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects, and is under clinical investigation for the treatment of advanced solid tumor and hematologic malignancies. However, the role of ALS in the treatment of ovarian cancer remains unclear. This study investigated the effects of ALS on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT), and the underlying mechanisms in human epithelial ovarian cancer SKOV3 and OVCAR4 cells. Our docking study showed that ALS, MLN8054, and VX-680 preferentially bound to AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS had potent growth-inhibitory, proapoptotic, proautophagic, and EMT-inhibitory effects on SKOV3 and OVCAR4 cells. ALS arrested SKOV3 and OVCAR4 cells in G2/M phase and induced mitochondria-mediated apoptosis and autophagy in both SKOV3 and OVCAR4 cell lines in a concentration-dependent manner. ALS suppressed phosphatidylinositol 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways but activated 5'-AMP-dependent kinase, as indicated by their altered phosphorylation, contributing to the proautophagic activity of ALS. Modulation of autophagy altered basal and ALS-induced apoptosis in SKOV3 and OVCAR4 cells. Further, ALS suppressed the EMT-like phenotype in both cell lines by restoring the balance between E-cadherin and N-cadherin. ALS downregulated sirtuin 1 and pre-B cell colony enhancing factor (PBEF/visfatin) expression levels and inhibited phosphorylation of AURKA in both cell lines. These findings indicate that ALS blocks the cell cycle by G2/M phase arrest and promotes cellular apoptosis and autophagy, but inhibits EMT via phosphatidylinositol 3-kinase/Akt/mTOR-mediated and sirtuin 1-mediated pathways in human epithelial ovarian cancer cells. Further studies are warranted to validate the efficacy and safety of ALS in the treatment of ovarian cancer.
Language eng
DOI 10.2147/DDDT.S74062
Field of Research 111501 Basic Pharmacology
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2015, Dove Medical Press
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30073295

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.