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Biol Pharm Bull ; 33(2): 168-73, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20118535

RESUMO

The resorcylic acid lactone hypothemycin has been shown to inactivate protein kinases by binding to a cysteine conserved in 46 protein kinases, including mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and platelet-derived growth factor receptor (PDGFR). We assessed the selectivity of hypothemycin in cellular contexts. Hypothemycin normalized the morphology and inhibited anchorage-independent growth of Ki-ras transformed normal rat kidney (NRK) cells with selectivity and potency comparable to or greater than that of the MEK inhibitor U0126. In Ki-ras-transformed and phorbol 12-myristate 13-acetate (PMA)-treated NRK cells, hypothemycin blocked ERK activation but showed a minimal effect on autophosphorylation of protein kinase D1 (PKD1), another kinase containing the conserved cysteine. Hypothemycin potently inhibited PDGFR autophosphorylation and activation of the MEK-ERK pathway in platelet-derived growth factor (PDGF)-treated NRK cells. However, the phosphoinositide-3-kinase (PI3K) pathway was only modestly attenuated. Hypothemycin also inhibited growth factor- and anchorage-independent growth of human cancer cell lines with a constitutively active MEK-ERK pathway. Although hypothemycin has the potential to inactivate various protein kinases, the results indicate that in intracellular environments, hypothemycin can inhibit the MEK-ERK axis with sufficient selectivity to normalize transformed phenotypes of cells dependent on this pathway.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Animais , Butadienos/farmacologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Flavonoides/farmacologia , Inibidores do Crescimento/farmacologia , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/enzimologia , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ratos , Zearalenona/análogos & derivados , Zearalenona/farmacologia
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