Modulation by melatonin of the cardiotoxic and antitumor activities of adriamycin.
In this study, we investigated the effects of melatonin on adriamycin-induced cardiotoxicity both in vivo in rats and in vitro, and on the antitumor activities of adriamycin on MDA-231 and NCI breast cancer cells. Rats that received a single intraperitoneal injection of 25 mg/kg adriamycin showed a mortality rate of 86%, which was reduced to 20% by melatonin treatment (10 mg/kg, SC for 6 days). Melatonin attenuated adriamycin-induced body-weight loss, hemodynamic dysfunction, and the morphologic and biochemical alterations caused by adriamycin. Melatonin also reduced adriamycin-induced nuclear DNA fragmentation, as assessed by the comet assay. In addition, the antitumor activity of adriamycin could be maintained using lower doses of this drug in combination with melatonin. Melatonin treatment in the concentration range of 0.1-2.5 mM inhibited the growth of human breast cancer cells. In terms of oncolytic activity, the combination of adriamycin and melatonin improved the antitumor activity of adriamycin, as indicated by an increase in the number of long-term survivors as well as decreases in body-weight losses resulting from adriamycin treatment. These results indicate that melatonin not only protects against adriamycin-induced cardiotoxicity but also enhances its antitumor activity. This combination of melatonin and adriamycin represents a potentially useful regimen for the treatment of human neoplasms because it allows the use of lower doses of adriamycin, thereby avoiding the toxic side effects associated with this drug.
Kim
Chunghui
C
Mitochondrial Signaling Laboratory, Department of Physiology and Biophysics, College of Medicine, Cardiovascular & Metabolic Disease Center, Biohealth Products Research Center, Inje University, Busan, Korea.
Kim
Nari
N
Joo
Hyun
H
Youm
Jae Boum
JB
Park
Won Sun
WS
Cuong
Dang Van
DV
Park
Young Shik
YS
Kim
Euiyong
E
Min
Churl-Ki
CK
Han
Jin
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014410:Tumor Stem Cell Assay
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D008550:Melatonin