PMID- 14678996
OWN - NLM
STAT- MEDLINE
DCOM- 20040227
LR  - 20091119
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 63
IP  - 23
DP  - 2003 Dec 1
TI  - Cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs inhibit 
      hepatocyte growth factor/scatter factor-induced angiogenesis.
PG  - 8351-9
AB  - Epidemiological studies have indicated a reduced risk of malignancies with the 
      use of nonsteroidal anti-inflammatory drugs (NSAIDs), although the exact 
      mechanisms are debated. NSAIDs inhibit angiogenesis, which is a key step for 
      tumor growth. Hepatocyte growth factor/scatter factor (HGF/SF), a potent and 
      independent angiogenic factor, has been implicated in tumorigenesis, but limited 
      knowledge exists on the potential targets for inhibiting HGF/SF-induced 
      pathological angiogenesis. The current study was designed to elucidate the 
      possible role of cyclooxygenase (COX) downstream of HGF/SF during angiogenesis 
      and to evaluate the potential for harnessing NSAIDs as a therapeutic strategy. 
      Known NSAIDs were classified as COX-1 or COX-2 selective based on their activity 
      in a platelet aggregation experiment. The inhibitors were administered into a 
      polyether polyurethane scaffold implant in mice at the selected doses, and the 
      total neovascularization after the administration of HGF/SF was quantified using 
      a (133)Xenon clearance technique, vessel counts, and immunohistochemistry. 
      Angiogenesis was also quantized into chemoinvasion, migration, proliferation, and 
      tube formation events in vitro, and the effects of the NSAIDs were evaluated on 
      HGF/SF-induced activity of human umbilical vein endothelial cells (HUVECs). 
      HGF/SF accelerated the angiogenic process in the murine implant, and this 
      activity was inhibited by COX-2-selective meloxicam and NS398. The COX-1 
      inhibitors ketoprofen and SC560 failed to inhibit the HGF/SF-induced angiogenic 
      events in vitro and in vivo. A COX-2 blockade inhibited the HGF/SF-induced 
      chemoinvasion and migration of human umbilical vein endothelial cells, without 
      affecting the proliferative or tubulogenic responses. Western blots revealed the 
      induction COX-2 expression after HGF/SF treatment, and the pharmacological 
      inhibition of COX-2 executed a temporal inhibition of phosphorylation of the 
      mitogen-activated protein kinases. The current study, for the first time, 
      implicates COX-2 as a downstream signal during HGF/SF-induced angiogenesis, 
      temporally impinging on the mitogen-activated protein kinase signaling. However, 
      the mediation is restricted to only the early events of the angiogenic process, 
      emphasizing the chemopreventive role for NSAIDs. Few therapeutic options 
      currently exist for HGF/SF-induced pathological angiogenesis, and the vast 
      knowledge on COX-2 inhibitors can be harnessed to design a newer therapeutic 
      approach.
FAU - Sengupta, Shiladitya
AU  - Sengupta S
AD  - Department of Pharmacology, Glaxo Institute of Applied Pharmacology, University 
      of Cambridge, Cambridge, United Kingdom.
FAU - Sellers, Lynda A
AU  - Sellers LA
FAU - Cindrova, Tereza
AU  - Cindrova T
FAU - Skepper, Jeremy
AU  - Skepper J
FAU - Gherardi, Ermanno
AU  - Gherardi E
FAU - Sasisekharan, Ram
AU  - Sasisekharan R
FAU - Fan, Tai-Ping D
AU  - Fan TP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Isoenzymes)
RN  - 0 (Lipoxygenase Inhibitors)
RN  - 0 (Membrane Proteins)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 1.13.11.12 (Lipoxygenase)
RN  - EC 1.14.99.1 (Cyclooxygenase 1)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.14.99.1 (PTGS1 protein, human)
RN  - EC 1.14.99.1 (PTGS2 protein, human)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
RN  - EC 1.14.99.1 (Ptgs1 protein, mouse)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Angiogenesis Inhibitors/*pharmacology
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Cell Division/drug effects
MH  - Cyclooxygenase 1
MH  - Cyclooxygenase 2
MH  - Cyclooxygenase 2 Inhibitors
MH  - Cyclooxygenase Inhibitors/*pharmacology
MH  - Endothelium, Vascular/cytology/drug effects/enzymology
MH  - Hepatocyte Growth Factor/*antagonists & inhibitors/pharmacology/physiology
MH  - Humans
MH  - Isoenzymes/*antagonists & inhibitors/biosynthesis
MH  - Lipoxygenase/metabolism
MH  - Lipoxygenase Inhibitors/pharmacology
MH  - Male
MH  - Membrane Proteins
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Neovascularization, Physiologic/*drug effects
MH  - Phosphorylation
MH  - Prostaglandin-Endoperoxide Synthases/biosynthesis
EDAT- 2003/12/18 05:00
MHDA- 2004/02/28 05:00
CRDT- 2003/12/18 05:00
PHST- 2003/12/18 05:00 [pubmed]
PHST- 2004/02/28 05:00 [medline]
PHST- 2003/12/18 05:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2003 Dec 1;63(23):8351-9.