Lyn is a target gene for prostate cancer: sequence-based inhibition induces regression of human tumor xenografts.
Cancer Res
; 64(3): 1058-66, 2004 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-14871838
ABSTRACT
The Src-related protein kinase Lyn plays an important role in B-cell activation. However, several lines of evidence suggest that it is also involved in the control of cellular proliferation and the inhibition of apoptosis. We have discovered that Lyn is expressed in normal prostate epithelia, in 95% of primary human prostate cancer (PC) specimens examined, and in all of the PC cell lines that we assayed. Moreover, Lyn knockout mice display abnormal prostate gland morphogenesis, which suggests that Lyn plays an important role in prostate epithelium development and implies that Lyn is a candidate target for specific therapy for PC. Using a drug-design strategy to construct sequence-based peptide inhibitors, a Lyn-specific inhibitor, KRX-123, targeting a unique interaction site within Lyn, was synthesized. KRX-123 was found to inhibit cellular proliferation in three hormone-refractory PC cell lines, DU145, PC3, and TSU-Pr1 with IC(50) values of 2-4 micro M. In vivo, tumor volume of DU145 explants in nude mice was significantly reduced after once-a-week injections of KRX-123, at a dose of 10 mg/kg, for a period of 5 weeks. Histological analyses of the treated tumors indicated extensive apoptosis. Thus, we suggest that Lyn inhibition may serve as a prime target for the treatment of hormone-refractory PC.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos
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Neoplasias de la Próstata
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Familia-src Quinasas
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Inhibidores Enzimáticos
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cancer Res
Año:
2004
Tipo del documento:
Article
País de afiliación:
Israel