Novel actions of tyrphostin AG 879: inhibition of RAF-1 and HER-2 expression combined with strong antitumoral effects on breast cancer cells.
Binding of growth factors to cell surface receptors activates protein tyrosine kinases (PTKs) that initiate cascades of downstream signaling events including the mitogen-activated protein (MAP) kinase cascade. This study reports that the PTK inhibitor AG 879 inhibits proliferation of human breast cancer cells through an effect involving inhibition of MAP kinase activation, but which cannot be explained by effects of AG 879 on its known PTK targets. Instead, AG 879 markedly inhibits expression of the RAF-1 gene, which encodes an upstream MAP kinase kinase kinase. Additionally, expression of HER-2, but not of other genes tested, is inhibited by this compound. These novel effects have to be considered when using AG 879 as a TRK-A and HER-2 inhibitor but may have useful therapeutic implications.
Larsson
L-I
LI
Anatomy and Cell Biology, IBHV, KVL, Gronnegaardsvej 7, 1870, Copenhagen, Denmark. lail@kvl.dk
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C081020:AG-879