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Pifithrin- protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice

¹Department of Pharmacology and ²Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State University; and James H. Quillen Veterans Affairs Medical Center, Johnson City, Tennessee 37614

Submitted 7 August 2003 ; accepted in final form 3 November 2003

The present experiments were designed to evaluate the effects of pifithrin- (PFT-), 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- 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- 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-. DOX gave rise to increased apoptosis-positive nuclei in cardiac cells, elevated serum creatine phosphokinase, ultrastructural alterations, and cardiac dysfunction. PFT- offered protection against all of the aforementioned changes. Finally, PFT- did not interfere with the antitumor potency of DOX. This study demonstrates that PFT- effectively inhibits DOX-induced cardiomyocyte apoptosis, which suggests that PFT- has the potential to protect cancer patients against DOX-induced cardiac injury.

p53; cardiac function; ultrastructural alterations

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