Liu Xuwan, Chua Chu C, Gao Jinping, Chen Zhongyi, Landy Cathy L C, Hamdy Ronald, Chua Balvin H L
PO Box 70,432, Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State Univ., Johnson City, TN 37614, USA.
Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H933-9. doi: 10.1152/ajpheart.00759.2003.
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.
本实验旨在评估p53抑制剂pifithrin-α（PFT-α）对阿霉素（DOX）诱导的细胞凋亡和心脏损伤的影响。给小鼠腹腔注射DOX（22.5mg/kg）可上调Bax和MDM2的mRNA水平，而在DOX攻击前30分钟和攻击后3小时以4.4mg/kg的总剂量给予PFT-α时，可减弱这些水平。DOX治疗导致p53蛋白水平上调，在此之前Ser15位点的磷酸化p53水平升高。PFT-α对p53水平或其磷酸化形式没有影响。DOX可使Bax和MDM2的蛋白水平升高，而PFT-α可使其减弱。DOX导致心脏细胞中凋亡阳性细胞核增加、血清肌酸磷酸激酶升高、超微结构改变和心脏功能障碍。PFT-α可防止所有上述变化。最后，PFT-α不干扰DOX的抗肿瘤效力。本研究表明，PFT-α有效抑制DOX诱导的心肌细胞凋亡，这表明PFT-α有潜力保护癌症患者免受DOX诱导的心脏损伤。
