PMID- 30080692
OWN - NLM
STAT- MEDLINE
DCOM- 20191017
LR  - 20220601
IS  - 1473-5741 (Electronic)
IS  - 0959-4973 (Linking)
VI  - 29
IP  - 10
DP  - 2018 Nov
TI  - VX-680 induces p53-mediated apoptosis in human cholangiocarcinoma cells.
PG  - 1004-1010
LID - 10.1097/CAD.0000000000000682 [doi]
AB  - VX-680 is one selective small-molecule inhibitor of the Aurora kinases. It has 
      been shown to disrupt motosis and induce apoptosis in a wide variety of tumor 
      cell lines. However, its effect on human cholangiocarcinoma (CCA) cells remains 
      uncharacterized. In the current study, we observed the effects of VX-680 on the 
      human CCA (QBC939 and HCCC-9810) cell line. In cell culture, VX-680 inhibited 
      proliferation and induced apoptosis of tumor cell growth in a dose-dependent and 
      time-dependent manner, and exerted the most effective cytotoxicity against 
      HCCC-9810 cells. The proliferation inhibition rate increased from 5.39 to 51.74%, 
      whereas the apoptosis rate increased from 9.59 to 50.02% when HCCC-9810 cells 
      were cultured with 5 micromol/l VX-680 for 48 h. Immunoblot analysis showed that the 
      expression of phospho-p53(Ser-15) was upregulated after 48 h treatment of the 
      cancer cells with VX-680. This activation in p53 was associated with a decrease 
      in Bcl-2 and an increase in Bax, which led to the expression of its downstream 
      effectors (caspase-9 and caspase-3). We further found that pifithrin-alpha, a p53 
      inhibitor, attenuated the anticancer effects of VX-680 and downregulated the 
      expression of apotosis-related proteins (Bax and caspase-9). These results 
      suggest that VX-680 could mediate cell death by acting on a P53/Bax/ 
      caspase-3-dependent pathway in human CCA cells.
FAU - Liu, Juan
AU  - Liu J
AD  - Department of Gastroenterology, Shandong Provincial Hospital Affiliated to 
      Shandong University, Jinan, People's Republic of China.
FAU - Qin, Cheng-Yong
AU  - Qin CY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Anticancer Drugs
JT  - Anti-cancer drugs
JID - 9100823
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 234335M86K (tozasertib)
RN  - EC 2.7.11.1 (Aurora Kinases)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (CASP9 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Aurora Kinases/antagonists & inhibitors
MH  - Bile Duct Neoplasms/*drug therapy
MH  - Caspase 3/metabolism
MH  - Caspase 9/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cholangiocarcinoma/*drug therapy/pathology
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Piperazines/administration & dosage/*pharmacology
MH  - Protein Kinase Inhibitors/administration & dosage/pharmacology
MH  - Time Factors
MH  - Tumor Suppressor Protein p53/*metabolism
EDAT- 2018/08/07 06:00
MHDA- 2019/10/18 06:00
CRDT- 2018/08/07 06:00
PHST- 2018/08/07 06:00 [pubmed]
PHST- 2019/10/18 06:00 [medline]
PHST- 2018/08/07 06:00 [entrez]
AID - 10.1097/CAD.0000000000000682 [doi]
PST - ppublish
SO  - Anticancer Drugs. 2018 Nov;29(10):1004-1010. doi: 10.1097/CAD.0000000000000682.