Modulation by Melatonin of the Cardiotoxic and Antitumor Activities of Adriamycin

Abstract

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.

Urinary Excretion of Melatonin and Association with Breast Cancer: Meta-Analysis and Review of the Literature

“…Melatonin was also found to protect animals from adriamycin-induced cardiotoxicity, while co-administration of both substances seems to enhance cytotoxic effects, thereby allowing for dose reductions and attenuation of undesirable side effects [16]. However, a variety of receptor-independent anti-carcinogenic effects of melatonin, such as free radical scavenging via antioxidant properties and modulation of immune functions [17], might exist as well that render the drug potentially useful in the treatment of other diseases.…”

Melatonin increased vitamin C and antioxidant enzyme values in the plasma,heart, liver, and kidney of Adriamycin-treated rats

“…The antioxidant activity of melatonin has been described to occur by two different mechanisms: (1) melatonin directly scavenges •OH radicals (Kim et al, 2005) and (2) melatonin reduces oxidative stress by stimulating antioxidant enzymes (Reiter et al, 1997). Oxidative stress is characterized as an imbalance between antioxidant defense systems and reactive oxygen species (ROS) generated during many aerobic physiological processes such as mitochondrial electron transfer reactions, phagocytic activity, and nitrogen reactive substances (Nazıroğlu, 2007(Nazıroğlu, , 2009.…”

“…NADPH-dependent reductase converts Adriamycin to semiquinone free reactive radicals (Vora et al, 1996). Increasing of these radicals during biotransformation of Adriamycin may play a major role in Adriamycin-induced toxicity (Monti et al, 1996;Vora et al, 1996), causing oxidative stress of cellular components in cardiac (Kim et al, 2005;Özdoğan et al, 2011;Zang et al, 2013), hepatic (Aydoğan et al, 2013;Lee et al, 2013), and renal tissues (Hrenak et al, 2013;Escribano et al, 2014).…”

Effect of Naringin on the DNA Damage Induced by Daunorubicin in Mouse Hepatocytes and Cardiocytes

“…With these two purposes in mind, several agents have been experimentally tested showing variable results; recently, administering vitamin E, melatonin, tomato-oleoresin, and rutoside-type flavonoids to mice or rats has given positive promising results. [27][28][29][30] A problem to solve in this type of studies is finding the appropriate dose and duration of exposure.…”