Pifithrin-α Protects Against Doxorubicin-Induced Apoptosis and Acute Cardiotoxicity in Mice
Document Type
Article
Publication Date
1-1-2004
Description
The present experiments were designed to evaluate the effects of pifithrin-α (PFT-α), 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-α 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-α 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-α. DOX gave rise to increased apoptosis-positive nuclei in cardiac cells, elevated serum creatine phosphokinase, ultrastructural alterations, and cardiac dysfunction. PFT-α offered protection against all of the aforementioned changes. Finally, PFT-α did not interfere with the antitumor potency of DOX. This study demonstrates that PFT-α effectively inhibits DOX-induced cardiomyocyte apoptosis, which suggests that PFT-α has the potential to protect cancer patients against DOX-induced cardiac injury.
Citation Information
Liu, Xuwan; Chua, Chu C.; Gao, Jinping; Chen, Zhongyi; Landy, Cathy L.C.; Hamdy, Ronald; and Chua, Balvin H.L.. 2004. Pifithrin-α Protects Against Doxorubicin-Induced Apoptosis and Acute Cardiotoxicity in Mice. American Journal of Physiology - Heart and Circulatory Physiology. Vol.286(3 55-3). https://doi.org/10.1152/ajpheart.00759.2003 PMID: 14766674 ISSN: 0363-6135