PMID- 19939254
OWN - NLM
STAT- MEDLINE
DCOM- 20100202
LR  - 20211020
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 9
DP  - 2009 Nov 25
TI  - PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth 
      factor-stimulated migration and proliferation of c-Met-positive neuroblastoma 
      cells.
PG  - 411
LID - 10.1186/1471-2407-9-411 [doi]
AB  - BACKGROUND: c-Met is a tyrosine kinase receptor for hepatocyte growth 
      factor/scatter factor (HGF/SF), and both c-Met and its ligand are expressed in a 
      variety of tissues. C-Met/HGF/SF signaling is essential for normal embryogenesis, 
      organogenesis, and tissue regeneration. Abnormal c-Met/HGF/SF signaling has been 
      demonstrated in different tumors and linked to aggressive and metastatic tumor 
      phenotypes. In vitro and in vivo studies have demonstrated inhibition of 
      c-Met/HGF/SF signaling by the small-molecule inhibitor PHA665752. This study 
      investigated c-Met and HGF expression in two neuroblastoma (NBL) cell lines and 
      tumor tissue from patients with NBL, as well as the effects of PHA665752 on 
      growth and motility of NBL cell lines. The effect of the tumor suppressor protein 
      PTEN on migration and proliferation of tumor cells treated with PHA665752 was 
      also evaluated. METHODS: Expression of c-Met and HGF in NBL cell lines SH-EP and 
      SH-SY5Y and primary tumor tissue was assessed by immunohistochemistry and 
      quantitative RT-PCR. The effect of PHA665752 on c-Met/HGF signaling involved in 
      NBL cell proliferation and migration was evaluated in c-Met-positive cells and 
      c-Met-transfected cells. The transwell chemotaxis assay and the MTT assay were 
      used to measure migration and proliferation/cell-survival of tumor cells, 
      respectively. The PPAR-gamma agonist rosiglitazone was used to assess the effect 
      of PTEN on PHA665752-induced inhibition of NBL cell proliferation/cell-survival 
      and migration RESULTS: High c-Met expression was detected in SH-EP cells and 
      primary tumors from patients with advanced-stage disease. C-Met/HGF signaling 
      induced both migration and proliferation of SH-EP cells. Migration and 
      proliferation/cell-survival were inhibited by PHA665752 in a dose-dependent 
      manner. We also found that induced overexpression of PTEN following treatment 
      with rosiglitazone significantly enhanced the inhibitory effect of PHA665752 on 
      NBL-cell migration and proliferation. CONCLUSION: c-Met is highly expressed in 
      most tumors from patients with advanced-stage, metastatic NBL. Furthermore, using 
      the NBL cell line SH-EP as a model, PHA665752 was shown to inhibit cMet/HGF/SF 
      signaling in vitro, suggesting c-Met inhibitors may have efficacy for blocking 
      local progression and/or metastatic spread of c-Met-positive NBL in vivo. These 
      are novel findings for this disease and suggest that further studies of agents 
      targeting the c-Met/HGF axis in NBL are warranted.
FAU - Crosswell, Hal E
AU  - Crosswell HE
AD  - Division of Pediatric Hematology/Oncology, Children's Hospital and University 
      Medical Group of the Greenville Hospital System, Greenville, SC 29605, USA. 
      HCrosswell@ghs.org
FAU - Dasgupta, Anindya
AU  - Dasgupta A
FAU - Alvarado, Carlos S
AU  - Alvarado CS
FAU - Watt, Tanya
AU  - Watt T
FAU - Christensen, James G
AU  - Christensen JG
FAU - De, Pradip
AU  - De P
FAU - Durden, Donald L
AU  - Durden DL
FAU - Findley, Harry W
AU  - Findley HW
LA  - eng
GR  - CA94233/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091125
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 
      (5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Indoles)
RN  - 0 (Sulfones)
RN  - 0 (Thiazolidinediones)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Indoles/*pharmacology
MH  - MAP Kinase Signaling System/drug effects
MH  - Neoplasm Staging
MH  - Neuroblastoma/*metabolism/pathology
MH  - PTEN Phosphohydrolase/metabolism
MH  - Proto-Oncogene Proteins c-met/drug effects/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Rosiglitazone
MH  - Sulfones/*pharmacology
MH  - Thiazolidinediones/pharmacology
MH  - Transfection
PMC - PMC2790467
EDAT- 2009/11/27 06:00
MHDA- 2010/02/03 06:00
PMCR- 2009/11/25
CRDT- 2009/11/27 06:00
PHST- 2008/12/31 00:00 [received]
PHST- 2009/11/25 00:00 [accepted]
PHST- 2009/11/27 06:00 [entrez]
PHST- 2009/11/27 06:00 [pubmed]
PHST- 2010/02/03 06:00 [medline]
PHST- 2009/11/25 00:00 [pmc-release]
AID - 1471-2407-9-411 [pii]
AID - 10.1186/1471-2407-9-411 [doi]
PST - epublish
SO  - BMC Cancer. 2009 Nov 25;9:411. doi: 10.1186/1471-2407-9-411.