PMID- 10591141
OWN - NLM
STAT- MEDLINE
DCOM- 19991222
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 58
IP  - 12
DP  - 1999 Dec 15
TI  - Selective inhibition of protein kinase C, mitogen-activated protein kinase, and 
      neutrophil activation in response to calcium pyrophosphate dihydrate crystals, 
      formyl-methionyl-leucyl-phenylalanine, and phorbol ester by 
      O-(chloroacetyl-carbamoyl) fumagillol (AGM-1470; TNP-470).
PG  - 1869-80
AB  - The effect of O-(chloroacetyl-carbamoyl) fumagillol (AGM-1470; TNP-470) was 
      investigated on protein kinase C (PKC) and mitogen-activated protein kinase 
      (MAPK) activation in neutrophils stimulated by plasma-opsonized crystals of 
      calcium pyrophosphate dihydrate (triclinic) [CPPD(T)], formyl-Met-Leu-Phe (fMLP), 
      and phorbol 12-myristate 13-acetate (PMA). Neutrophil respiratory burst responses 
      also were determined in AGM-1470-pretreated cells stimulated with the same 
      agonists, using chemiluminescence and superoxide anion generation assays. 
      AGM-1470 (5 microM) effectively inhibited PKC activation in cells treated with 
      CPPD(T) crystals (50 mg/mL, 2 min) and fMLP (1 microM, 1 min), but had no effect 
      on PMA-treated cells (0.5 microM, 5 min). AGM-1470 blocked MAPK activity 
      completely and reduced neutrophil activation induced by fMLP and PMA but not by 
      CPPD(T). The degree of inhibition of the respiratory burst plateaued at 
      approximately 46+/-9 and 54+/-3% in fMLP- and PMA-treated cells, respectively. 
      These data indicate that activation of neutrophil respiratory burst activity may 
      be mediated through the MAPK pathway. AGM-1470 pretreatment did not inhibit 
      CPPD(T) crystal- or fMLP-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) 
      activity. These findings, coupled with further observations that the PI 3-kinase 
      inhibitor wortmannin (10 nM) inhibited fMLP- and CPPD(T) crystal-induced but not 
      PMA-induced chemiluminescence, indicate that at least two distinct signaling 
      pathways (mediated by PI 3-kinase or MAPK) lead to neutrophil respiratory burst 
      responses. PKC may also be required in the MAPK-stimulated pathway. We propose 
      that the inhibitory effect of AGM-1470 on the neutrophil respiratory burst may be 
      due to its ability to inhibit PKC and MAPK activation.
FAU - Tudan, C
AU  - Tudan C
AD  - BioChem Pharma, Laval, Quebec, Canada.
FAU - Jackson, J K
AU  - Jackson JK
FAU - Pelech, S L
AU  - Pelech SL
FAU - Attardo, G
AU  - Attardo G
FAU - Burt, H
AU  - Burt H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Carcinogens)
RN  - 0 (Cyclohexanes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Sesquiterpenes)
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
RN  - X47GR46481 (O-(Chloroacetylcarbamoyl)fumagillol)
RN  - X69NU20D19 (Calcium Pyrophosphate)
SB  - IM
MH  - Calcium Pyrophosphate/*pharmacology
MH  - Carcinogens/pharmacology
MH  - Cyclohexanes
MH  - Drug Interactions
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors
MH  - N-Formylmethionine Leucyl-Phenylalanine/*pharmacology
MH  - *Neutrophil Activation
MH  - Neutrophils/*drug effects/enzymology
MH  - O-(Chloroacetylcarbamoyl)fumagillol
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Kinase C/*antagonists & inhibitors
MH  - Sesquiterpenes/*pharmacology
MH  - Tetradecanoylphorbol Acetate/*pharmacology
EDAT- 1999/12/11 00:00
MHDA- 1999/12/11 00:01
CRDT- 1999/12/11 00:00
PHST- 1999/12/11 00:00 [pubmed]
PHST- 1999/12/11 00:01 [medline]
PHST- 1999/12/11 00:00 [entrez]
AID - S0006-2952(99)00287-7 [pii]
AID - 10.1016/s0006-2952(99)00287-7 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1999 Dec 15;58(12):1869-80. doi: 
      10.1016/s0006-2952(99)00287-7.