erbstatin and Carcinoma--Squamous-Cell

We have reported the in vitro and in vivo anticancer activities of 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) derived from a Japanese spice, wasabi. In order to obtain some clues about the mechanism of the anticancer activity, we have studied the effect of alkyl isothiocyanates (MITCs) on protein kinase activities.. The anti-autophosphorylation activity of MITCs with respect to the epidermal growth factor (EGF)-stimulated receptor kinase of A431 epidermoid carcinoma cells was examined by incorporation of radioactive ATP into an acid-insoluble fraction. Their anti-phosphorylation activity with respect to the non-receptor protein kinase was analyzed by a standard SDS-PAGE method.. All the tested MITCs interfered with the EGF-stimulated receptor kinase activity in a dose-dependent manner, although their effects were less than 1/10 of that of erbstatin in microg/ml. On the other hand, the MITCs did not interfere with non-receptor kinases (kinase A, kinase C, tyrosine kinase and calmodulin dependent kinase III), but enhanced non-receptor tyrosine kinase.. A possible anticancer mechanism of MITCs may involve the suppression of EGF receptor kinase activity and augmentation of non-receptor PTK.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; ErbB Receptors; Humans; Hydroquinones; Isothiocyanates; K562 Cells; Phosphorylation; Protein-Tyrosine Kinases

Topics: Arachidonate 12-Lipoxygenase; Arachidonic Acid; Carcinoma, Squamous Cell; Enzyme Induction; Enzyme Inhibitors; Epidermal Growth Factor; Humans; Hydroquinones; Isoenzymes; Microsomes; Protein Kinase C; Protein-Tyrosine Kinases; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

A novel class of low molecular weight protein tyrosine kinase inhibitors is described. These compounds constitute a systematic series of molecules with a progressive increase in affinity toward the substrate site of the EGF receptor kinase domain. These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor. The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptor kinase at 10(2)-10(3) higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases. These results demonstrate the ability to synthesize selective tyrosine kinase inhibitors. The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth. These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases. We have suggested the name "tyrphostins" for this class of antiproliferative compounds which act as protein tyrosine kinase blockers.

Topics: Benzylidene Compounds; Carcinoma, Squamous Cell; Cell Division; Cell Line; Epidermal Growth Factor; ErbB Receptors; Humans; Kinetics; Molecular Structure; Nitriles; Phosphorylation; Protein-Tyrosine Kinases; Structure-Activity Relationship

Topics: Actinomycetales; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Cell Line; ErbB Receptors; Humans; Hydroquinones; Microbial Sensitivity Tests; Protein-Tyrosine Kinases; Receptors, Cell Surface; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet