Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt.
Clin Cancer Res
; 14(22): 7511-8, 2008 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-19010869
ABSTRACT
PURPOSE:
To assess the safety of administering bortezomib to patients undergoing a radical prostatectomy, to assess pathologic changes induced by bortezomib in prostate cancer specimen, and to verify alterations by the drug in proteasome protein targets. EXPERIMENTALDESIGN:
Bortezomib is a proteasome inhibitor that has shown activity in vitro and in vivo in prostate cancer. We performed a neoadjuvant clinical trial of bortezomib in men with prostate cancer at high risk of recurrence. The primary endpoints were to evaluate safety and biological activity.RESULTS:
Bortezomib is generally safe in the preoperative setting. Antitumor activity was manifested by tumor cytopathic effect, drops in serum prostate-specific antigen in some patients, and increases in tumor apoptosis. This was associated with cytoplasmic entrapment of nuclear factor-kappaB. We found an unexpected increase in proliferation in treated tissues and in vitro. Bortezomib also increased SRC-3 levels and phosphorylated Akt, both in vitro and in treated prostate cancer tissues. Knockdown of SRC-3 blocked the increase in activated Akt in vitro. Combined treatment with bortezomib and the Akt inhibitor perifosine was more effective than either agent alone in vitro.CONCLUSION:
These data suggest that combined therapies targeting the proteasome and the Akt pathway may have increased efficacy.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
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Pirazinas
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Ácidos Borónicos
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Transactivadores
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Histona Acetiltransferasas
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Proteínas Proto-Oncogénicas c-akt
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Antineoplásicos
Límite:
Adult
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Aged
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Aged80
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2008
Tipo del documento:
Article