Melatonin as an effective protector against doxorubicin-induced cardiotoxicity.
The present study was designed to explore the protective effects of melatonin and its analogs, 6-hydroxymelatonin and 8-methoxy-2-propionamidotetralin, on the survival of doxorubicin-treated mice and on doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Whereas 60% of the mice treated with doxorubicin (25 mg/kg ip) died in 5 days, almost all the doxorubicin-treated mice survived when melatonin or 6-hydroxymelatonin (10 mg/l) was administered in their drinking water. Perfusion of mouse hearts with 5 microM doxorubicin for 60 min led to a 50% suppression of heart rate x left ventricular developed pressure and a 50% reduction of coronary flow. Exposure of hearts to 1 microM melatonin or 6-hydroxymelatonin reversed doxorubicin-induced cardiac dysfunction. 8-Methoxy-2-propionamidotetralin had no protective effects on animal survival and on in vitro cardiac function. Infusion of melatonin or 6-hydroxymelatonin (2.5 microg/h) significantly attenuated doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Neither melatonin nor 6-hydroxymelatonin compromised the antitumor activity of doxorubicin in cultured PC-3 cells. These results suggest that melatonin protect against doxorubicin-induced cardiotoxicity without interfering with its antitumor effect.
Liu
Xuwan
X
Department of Pharmacology, James H. Quillen School of Medicine, East Tennessee State University and James H. Quillen Veterans Affairs Medical Center, Johnson City, Tennessee 37614, USA.
Chen
Zhongyi
Z
Chua
Chu Chang
CC
Ma
Yan-Shan
YS
Youngberg
George A
GA
Hamdy
Ronald
R
Chua
Balvin H L
BH
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003402:Creatine Kinase / Q000097:blood; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D016277:Ventricular Function, Left / Q000187:drug effects
D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D004317:Doxorubicin; D003402:Creatine Kinase; D008550:Melatonin; C012365:6-hydroxymelatonin