Pifithrin-alpha protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice.
Am J Physiol Heart Circ Physiol
; 286(3): H933-9, 2004 Mar.
Article
em En
| MEDLINE
| ID: mdl-14766674
ABSTRACT
The present experiments were designed to evaluate the effects of pifithrin-alpha (PFT-alpha), which is a p53 inhibitor, on doxorubicin (DOX)-induced apoptosis and cardiac injury. Administration of DOX (22.5 mg/kg ip) in mice upregulated the mRNA levels of Bax and MDM2, whereas PFT-alpha attenuated those levels when administered at a total dose of 4.4 mg/kg at 30 min before and 3 h after DOX challenge. DOX treatment led to an upregulation of p53 protein levels, which was preceded by elevated levels of phosphorylated p53 at Ser15. PFT-alpha had no effect on the level of p53 or its phosphorylated form. The protein levels of Bax and MDM2 were elevated by DOX and attenuated by PFT-alpha. DOX gave rise to increased apoptosis-positive nuclei in cardiac cells, elevated serum creatine phosphokinase, ultrastructural alterations, and cardiac dysfunction. PFT-alpha offered protection against all of the aforementioned changes. Finally, PFT-alpha did not interfere with the antitumor potency of DOX. This study demonstrates that PFT-alpha effectively inhibits DOX-induced cardiomyocyte apoptosis, which suggests that PFT-alpha has the potential to protect cancer patients against DOX-induced cardiac injury.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
/
Tolueno
/
Doxorrubicina
/
Apoptose
/
Cardiopatias
/
Antibióticos Antineoplásicos
Limite:
Animals
Idioma:
En
Revista:
Am J Physiol Heart Circ Physiol
Assunto da revista:
CARDIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos