Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells.
Proc Natl Acad Sci U S A
; 102(17): 5998-6003, 2005 Apr 26.
Article
en En
| MEDLINE
| ID: mdl-15837920
ABSTRACT
Stat3 protein has an important role in oncogenesis and is a promising anticancer target. Indirubin, the active component of a traditional Chinese herbal medicine, has been shown previously to inhibit cyclin-dependent kinases, resulting in cell cycle arrest. Here, we show that the indirubin derivatives E564, E728, and E804 potently block constitutive Stat3 signaling in human breast and prostate cancer cells. In addition, E804 directly inhibits Src kinase activity (IC(50) = 0.43 microM) in an in vitro kinase assay. Levels of tyrosyl phosphorylation of c-Src are also reduced in cultured cells 30 min after E804 treatment. Tyrosyl phosphorylation of Stat3, which is known to be phosphorylated by c-Src, was decreased, and constitutive Stat3 DNA binding-activity was suppressed in cells 30 min after E804 treatment. The antiapoptotic proteins Mcl-1 and Survivin, which are encoded in target genes of Stat3, were down-regulated by indirubin derivatives, followed by induction of apoptosis. These results demonstrate that E804 directly blocks the Src-Stat3 signaling pathway, suggesting that the antitumor activity of indirubin compounds is at least partially due to inhibition of this pathway.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_breast_cancer
/
6_prostate_cancer
Asunto principal:
Transactivadores
/
Apoptosis
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Proteínas de Unión al ADN
/
Indoles
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos