PMID- 31575848
OWN - NLM
STAT- MEDLINE
DCOM- 20200302
LR  - 20211204
IS  - 1643-3750 (Electronic)
IS  - 1234-1010 (Print)
IS  - 1234-1010 (Linking)
VI  - 25
DP  - 2019 Oct 2
TI  - Tivantinib Hampers the Proliferation of Glioblastoma Cells via PI3K/Akt/Mammalian 
      Target of Rapamycin (mTOR) Signaling.
PG  - 7383-7390
LID - 10.12659/MSM.919319 [doi]
AB  - BACKGROUND Glioblastoma, the most common and malignant glial tumor, often has 
      poor prognosis. Tivantinib has shown its potential in treating c-Met-high 
      carcinoma. No studies have explored whether tivantinib inhibits the development 
      of glioblastoma. MATERIAL AND METHODS The correlation between c-Met expression 
      and clinicopathological characteristics of glioblastoma was investigated. U251 
      and T98MG glioblastoma cells treated with tivantinib, PI3K inhibitor (LY294002), 
      PI3K activator (740 Y-P), and/or mammalian target of rapamycin (mTOR) inhibitor 
      were subjected to MTT assay or colony formation assay to evaluate cell 
      proliferation. The expression of mTOR signaling and caspase-3 in 
      tivantinib-treated glioblastoma cells was differentially measured by western 
      blotting. RESULTS In a group of Chinese patients, expression of c-Met was 
      elevated with the size of glioblastoma, but not with the other 
      clinicopathological characteristics, including gender, age, grade, IDH status, 
      1p/19q status, and Ki67 status. High dose of tivantinib (1 mumol/L) obviously 
      repressed the proliferation and colony formation of U251 and T98MG glioblastoma 
      cells, but low dose (0.1 mumol/L) of tivantinib failed to retard cell 
      proliferation. Tivantinib blocked PI3K/Akt/mTOR signaling but did not change the 
      expression of cleaved caspase-3. PI3K activator 740 Y-P (20 mumol/L) significantly 
      rescued tivantinib-induced decrease of cell proliferation. Tivantinib (1 mumol/L) 
      in combination with PI3K inhibitor LY294002 (0.5 mumol/L) and mTOR inhibitor 
      rapamycin (0.1 nmol/L) largely inhibited the proliferation of glioblastoma cells. 
      CONCLUSIONS c-MET inhibitor tivantinib blocks PIKE/Akt/mTOR signaling and hampers 
      the proliferation of glioblastoma cells, which endows the drug a therapeutic 
      effect.
FAU - Wu, Yukun
AU  - Wu Y
AD  - Department of General Practice, Linyi Central Hospital, Yishui, Shandong, China 
      (mainland).
FAU - Li, Zhizhang
AU  - Li Z
AD  - Department of General Practice, Linyi Central Hospital, Yishui, Shandong, China 
      (mainland).
FAU - Zhang, Lijuan
AU  - Zhang L
AD  - Department of Cardiovascular Medicine, Linyi Central Hospital, Yishui, Shandong, 
      China (mainland).
FAU - Liu, Guiyang
AU  - Liu G
AD  - Department of Neurosurgery, Jinan Fourth People's Hospital, Jinan, Shandong, 
      China (mainland).
LA  - eng
PT  - Journal Article
DEP - 20191002
PL  - United States
TA  - Med Sci Monit
JT  - Medical science monitor : international medical journal of experimental and 
      clinical research
JID - 9609063
RN  - 0 (ARQ 197)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Pyrrolidinones)
RN  - 0 (Quinolines)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - China
MH  - Chromones/pharmacology
MH  - Female
MH  - Gene Expression
MH  - Glioblastoma/*drug therapy/pathology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-met/*metabolism/physiology
MH  - Pyrrolidinones/metabolism/*pharmacology
MH  - Quinolines/metabolism/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC6790099
COIS- Conflicts of interest None.
EDAT- 2019/10/03 06:00
MHDA- 2020/03/03 06:00
PMCR- 2019/10/02
CRDT- 2019/10/03 06:00
PHST- 2019/10/03 06:00 [entrez]
PHST- 2019/10/03 06:00 [pubmed]
PHST- 2020/03/03 06:00 [medline]
PHST- 2019/10/02 00:00 [pmc-release]
AID - 919319 [pii]
AID - 10.12659/MSM.919319 [doi]
PST - epublish
SO  - Med Sci Monit. 2019 Oct 2;25:7383-7390. doi: 10.12659/MSM.919319.