TY - JOUR
T1 - Inhibition of platelet-derived growth factor-induced mitogenesis and tyrosine kinase activity in cultured bone marrow fibroblasts by tyrphostins
AU - Bryckaert, Marie Claude
AU - Eldor, Amiram
AU - Fontenay, Michaëla
AU - Gazit, Aviv
AU - Osherov, Nir
AU - Gilon, Chaim
AU - Levitzki, Alexander
AU - Tobelem, Gerard
PY - 1992/4
Y1 - 1992/4
N2 - Tyrphostins, which block protein tyrosine kinase activity, were studied for their inhibitory action on platelet-derived growth factor (PDGF)-induced proliferation of human bone marrow fibroblasts. Of the seven tyrphostins examined, tyrphostin AG370 was found to be the most potent blocker against PDGF-induced mitogenesis (IC50 = 20 μM). This PTK blocker also blocks mitogenesis induced by epidermal growth factor (IC50 = 50 μM) and human serum (IC50 = 50 μM), but with lower efficacy. In digitonin-permeabilized fibroblasts as well as in intact fibroblasts, tyrphostin AG370 inhibits PDGF receptor autophosphorylation and the tyrosine phosphorylation of intracellular protein substrates (pp120, pp85, and pp75) which coprecipitate with the PDGF receptor. In comparison to AG370, AG18, a potent EGF receptor blocker, was less efficient in inhibiting PDGF-induced proliferation of fibroblasts and phosphorylation of the intracellular protein substrates. Under the conditions in which AG370 inhibits PDGF-induced mitogenesis and phosphorylation, it does not affect [125I]PDGF internalization and enhance [125I]-PDGF binding. These findings suggest that AG370, which is an indole tyrphostin, may serve as a model for developing analogues with a therapeutic potential for treatment of diseases which involve abnormal cellular proliferation induced by PDGF.
AB - Tyrphostins, which block protein tyrosine kinase activity, were studied for their inhibitory action on platelet-derived growth factor (PDGF)-induced proliferation of human bone marrow fibroblasts. Of the seven tyrphostins examined, tyrphostin AG370 was found to be the most potent blocker against PDGF-induced mitogenesis (IC50 = 20 μM). This PTK blocker also blocks mitogenesis induced by epidermal growth factor (IC50 = 50 μM) and human serum (IC50 = 50 μM), but with lower efficacy. In digitonin-permeabilized fibroblasts as well as in intact fibroblasts, tyrphostin AG370 inhibits PDGF receptor autophosphorylation and the tyrosine phosphorylation of intracellular protein substrates (pp120, pp85, and pp75) which coprecipitate with the PDGF receptor. In comparison to AG370, AG18, a potent EGF receptor blocker, was less efficient in inhibiting PDGF-induced proliferation of fibroblasts and phosphorylation of the intracellular protein substrates. Under the conditions in which AG370 inhibits PDGF-induced mitogenesis and phosphorylation, it does not affect [125I]PDGF internalization and enhance [125I]-PDGF binding. These findings suggest that AG370, which is an indole tyrphostin, may serve as a model for developing analogues with a therapeutic potential for treatment of diseases which involve abnormal cellular proliferation induced by PDGF.
UR - http://www.scopus.com/inward/record.url?scp=0026666967&partnerID=8YFLogxK
U2 - 10.1016/0014-4827(92)90432-8
DO - 10.1016/0014-4827(92)90432-8
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C2 - 1312007
AN - SCOPUS:0026666967
SN - 0014-4827
VL - 199
SP - 255
EP - 261
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 2
ER -