PMID- 25624750
OWN - NLM
STAT- MEDLINE
DCOM- 20150909
LR  - 20211203
IS  - 1177-8881 (Electronic)
IS  - 1177-8881 (Linking)
VI  - 9
DP  - 2015
TI  - Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but 
      inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer 
      cells.
PG  - 425-64
LID - 10.2147/DDDT.S74062 [doi]
AB  - 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 pi-pi 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.
FAU - Ding, Yong-Hui
AU  - Ding YH
AD  - Department of Gynecology, 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.
FAU - Zhou, Zhi-Wei
AU  - Zhou ZW
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of South 
      Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative 
      Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint 
      Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People's 
      Republic of China.
FAU - Ha, Chun-Fang
AU  - Ha CF
AD  - Department of Gynecology, General Hospital of Ningxia Medical University, 
      Yinchuan, People's Republic of China.
FAU - Zhang, Xue-Yu
AU  - Zhang XY
AD  - Department of Gynecology, General Hospital of Ningxia Medical University, 
      Yinchuan, People's Republic of China.
FAU - Pan, Shu-Ting
AU  - Pan ST
AD  - Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of 
      Nanchang University, Nanchang, People's Republic of China.
FAU - He, Zhi-Xu
AU  - He ZX
AD  - Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue 
      Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, 
      Guiyang Medical University, Guiyang, People's Republic of China.
FAU - Edelman, Jeffrey L
AU  - Edelman JL
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of South 
      Florida, Tampa, FL, USA.
FAU - Wang, Dong
AU  - Wang D
AD  - Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military 
      Medical University, Chongqing, People's Republic of China.
FAU - Yang, Yin-Xue
AU  - Yang YX
AD  - Department of Colorectal Surgery, General Hospital of Ningxia Medical University, 
      Yinchuan, People's Republic of China.
FAU - Zhang, Xueji
AU  - Zhang X
AD  - Research Center for Bioengineering and Sensing Technology, University of Science 
      and Technology Beijing, Beijing, People's Republic of China.
FAU - Duan, Wei
AU  - Duan W
AD  - School of Medicine, Deakin University, Waurn Ponds, Australia.
FAU - Yang, Tianxin
AU  - Yang T
AD  - Department of Internal Medicine, University of Utah and Salt Lake Veterans 
      Affairs Medical Center, Salt Lake City, UT, USA.
FAU - Qiu, Jia-Xuan
AU  - Qiu JX
AD  - Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of 
      Nanchang University, Nanchang, People's Republic of China.
FAU - Zhou, Shu-Feng
AU  - Zhou SF
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of South 
      Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative 
      Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint 
      Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People's 
      Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150109
PL  - New Zealand
TA  - Drug Des Devel Ther
JT  - Drug design, development and therapy
JID - 101475745
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Azepines)
RN  - 0 (MLN 8237)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (AURKA protein, human)
RN  - EC 2.7.11.1 (Aurora Kinase A)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
MH  - Antineoplastic Agents/chemistry/metabolism/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Aurora Kinase A/*antagonists & inhibitors/chemistry/metabolism
MH  - Autophagy/*drug effects
MH  - Azepines/chemistry/metabolism/*pharmacology
MH  - Binding Sites
MH  - Carcinoma, Ovarian Epithelial
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Epithelial-Mesenchymal Transition/*drug effects
MH  - Female
MH  - G2 Phase Cell Cycle Checkpoints/drug effects
MH  - Humans
MH  - Hydrogen Bonding
MH  - Molecular Docking Simulation
MH  - Molecular Structure
MH  - Molecular Targeted Therapy
MH  - Neoplasms, Glandular and Epithelial/*enzymology/pathology
MH  - Ovarian Neoplasms/*enzymology/pathology
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Kinase Inhibitors/chemistry/metabolism/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyrimidines/chemistry/metabolism/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Sirtuin 1/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Time Factors
PMC - PMC4296919
OTO - NOTNLM
OT  - Aurora kinase A
OT  - alisertib
OT  - apoptosis
OT  - autophagy
OT  - cell cycle
OT  - epithelial ovarian cancer
OT  - epithelial to mesenchymal transition
OT  - sirtuin 1
EDAT- 2015/01/28 06:00
MHDA- 2015/09/10 06:00
PMCR- 2015/01/09
CRDT- 2015/01/28 06:00
PHST- 2015/01/28 06:00 [entrez]
PHST- 2015/01/28 06:00 [pubmed]
PHST- 2015/09/10 06:00 [medline]
PHST- 2015/01/09 00:00 [pmc-release]
AID - dddt-9-425 [pii]
AID - 10.2147/DDDT.S74062 [doi]
PST - epublish
SO  - Drug Des Devel Ther. 2015 Jan 9;9:425-64. doi: 10.2147/DDDT.S74062. eCollection 
      2015.