Hydroxyphenyl acetate derivatives inhibit protein tyrosine kinase activity and proliferation in Nb2 rat lymphoma cells and insulin-induced lipogenesis in rat adipocytes.
The ortho, meta, and para forms of hydroxyphenyl acetate were found to be inhibitory in the order of ortho greater than para greater than meta in three distinct biological assays: (a) insulin-dependent assimilation of glucose into lipids in intact adipocytes, (b) growth and proliferation of Nb2 rat lymphoma cells, and (c) tyrosine phosphorylation of copolymer (Glu4Tyr) under cell-free conditions. Although relatively high concentrations of o-hydroxyphenyl acetate (OHPA) were required to inhibit these processes, the inhibitor exhibited a low index of cytotoxicity and high specificity toward inhibiting tyrosine- (but not serine-) specific kinases. Cell cycle analysis of the DNA histograms in Nb2 cells revealed that exposure to OHPA did not change the initiation of the G0/G1----S transition but drastically reduced its rate and a subsequent cell proliferation. Kinetic experiments in which the inhibitor was added or withdrawn through different phases of cell cycle confirmed this conclusion. OHPA inhibition of cell growth appears to be limited to eukaryotic cells as the growth of either gram-positive or gram-negative bacteria was unaffected by the presence of the inhibitor. The study supports the following conclusions: (a) Events that are dependent on tyrosine phosphorylation are indeed essential for mammalian cell growth and proliferation. (b) Neither the initial nor intermediate events of the proliferative cascade that occur in the Nb2 cells prior to DNA synthesis are dependent on the activity of protein tyrosine kinase(s) that are inhibited by OHPA. (c) Cell growth of prokaryotic cells and yeast may lack protein tyrosine kinase activity or be less dependent on events requiring tyrosine phosphorylation. (d) Inhibition of the insulin-dependent lipogenesis is subsequent to the inhibition of insulin receptor tyrosine kinase activity.
Shechter
Y
Y
Department of Hormone Research, Weizmann Institute of Science, Rehovot, Israel.
Sakal
E
E
Cohen
R
R
Cohen-Chapnik
N
N
Gertler
A
A
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000502:physiology; D007700:Kinetics; D008055:Lipids / Q000096:biosynthesis*; D008223:Lymphoma; D010648:Phenylacetates / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D007328:Insulin; D008055:Lipids; D010648:Phenylacetates; C008070:4-hydroxyphenylacetic acid; D011505:Protein-Tyrosine Kinases