Pifithrin-alpha protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice.
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.
Liu
Xuwan
X
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.
Chua
Chu C
CC
Gao
Jinping
J
Chen
Zhongyi
Z
Landy
Cathy L C
CL
Hamdy
Ronald
R
Chua
Balvin H L
BH
D000208:Acute Disease; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D013844:Thiazoles / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D052160:Benzothiazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D004317:Doxorubicin; C121565:pifithrin; D003402:Creatine Kinase