Genistein analogues: effects on epidermal growth factor receptor tyrosine kinase and on stress-activated pathways

• Published in: Biomedicine & pharmacotherapy Vol. 51; no. 6; pp. 286 - 294
• Main Authors: Croisy-Delcey, M, Croisy, A, Mousset, S, Letourneur, M, Bisagni, E, Jacquemin-Sablon, A, Pierre, J
• Format: Journal Article
• Language: English
• Published: Paris Elsevier SAS 1997; Elsevier
• Subjects: Antineoplastic agents; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Chemotherapy; EGF receptor; Enzyme Inhibitors - pharmacology; ERK; Genistein; genistein analogues; In Vitro Techniques; Isoflavones - chemical synthesis; Isoflavones - chemistry; Isoflavones - pharmacology; JNK; JNK Mitogen-Activated Protein Kinases; Medical sciences; Mitogen-Activated Protein Kinases; Pharmacology. Drug treatments; Phosphorylation - drug effects; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - drug effects; Tumor Cells, Cultured; tyrosine kinase; genistein analogues; EGF receptor; JNK; tyrosine kinase; ERK; Antineoplastic agent; Enzyme; Transferases; Cytokine; Enzyme inhibitor; In vitro; Isoflavone derivatives; Signal transduction; Epidermal growth factor; Structure activity relation; Polypeptide; Established cell line; Mechanism of action; Protein-tyrosine kinase; Comparative study; Growth factor; Biological receptor
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/S0753-3322(97)83545-7

Two genistein analogues (MD831 and MD833) have been synthesized and analyzed for their biological properties and their mechanism of action in comparison to genistein either in vitro or in intact cells. We showed that, in vitro, one of these compounds (MD831) inhibits the tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) as efficiently as genistein. However, treatment of A431 cells with these compounds did not result in any significant modification of EGFR tyrosine phosphorylation. Extracellular-signal regulated kinase (ERK) phosphorylation in cells stimulated by EGF was enhanced in the presence of MD831, whereas the other compounds, genistein and MD833, were able to activate the c-jun N-terminal kinase (JNK). This study showed that two structurally related compounds could elicit markedly different pharmacological effects on two signalling pathways, one involved in the mitogenic response and the other in the stress response. Such compounds may be useful to characterize signalling events involved in cell response to physiological stimuli.