Pifithrin-α protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice
Pifithrin-α protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice
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DOI：
10.1152/ajpheart.00759.2003
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发表时间：
2004-03-01
影响因子：
4.8
通讯作者：
Chua, BHL
中科院分区：
文献类型：
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作者：
Liu, XW;Chua, C;Chua, BHL
本实验旨在评估p53抑制剂pifithrin-alpha（PFT-alpha）对阿霉素（DOX）诱导的细胞凋亡和心脏损伤的影响。在小鼠中给予DOX（22.5mg/kg ip）上调Bax和MDM 2的mRNA水平，而当在DOX激发前30分钟和激发后3小时以4.4mg/kg的总剂量给予PFT-α时，这些水平减弱。DOX治疗导致p53蛋白水平上调，这之前是丝氨酸15位磷酸化p53水平升高。PFT-α对p53或其磷酸化形式的水平没有影响。DOX可升高Bax和MDM 2的蛋白水平，而PFT-α可降低Bax和MDM 2的蛋白水平。DOX引起心肌细胞凋亡阳性细胞核增加、血清肌酸磷酸激酶升高、超微结构改变和心功能不全。PFT-alpha提供了针对所有上述变化的保护。最后，PFT-α不干扰DOX的抗肿瘤效力。这项研究表明，PFT-α有效地抑制了DOX诱导的心肌细胞凋亡，这表明PFT-α具有保护癌症患者免受DOX诱导的心脏损伤的潜力。
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.