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

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.

• Authors: Xuwan Liu, Chu C Chua, Jinping Gao, Zhongyi Chen, Cathy L C Landy, Ronald Hamdy, Balvin H L Chua
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 286 Issue 3 Pg. H933-9 (Mar 2004) ISSN: 0363-6135 [Print] United States
• PMID: 14766674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Benzothiazoles
• Thiazoles
• Tumor Suppressor Protein p53
• Toluene
• Doxorubicin
• pifithrin
• Creatine Kinase

Topics

• Acute Disease
• Animals
• Antibiotics, Antineoplastic (toxicity)
• Apoptosis (drug effects)
• Benzothiazoles
• Cell Line, Tumor
• Creatine Kinase (metabolism)
• Doxorubicin (toxicity)
• Gene Expression (drug effects)
• Heart (drug effects)
• Heart Diseases (chemically induced, pathology, prevention & control)
• Mice
• Mice, Inbred ICR
• Myocardium (pathology, ultrastructure)
• Thiazoles (pharmacology)
• Toluene (analogs & derivatives, pharmacology)
• Tumor Suppressor Protein p53 (genetics)