Comparative investigation of the efficiency of dexrazoxane and silymarin in rats with doxorubicin-induced cardiotoxicity

Anthracyclines, including Doxorubicin (DOX) and idarubicin, also known as Topoisomerase (Topo) 'poisons', are one of the most effective anti-cancer agents. Cardiotoxicity, commonly encountered adverse effect, may limit their use. DOX exert its effect on tumour cells mostly through inhibition of DNA TopIIα enzyme activity. Dexrazoxane (DEX) is the only clinically approved drug by the U.S. Food and Drug Administration (FDA) for the prevention of DOX-induced cardiotoxicity. Because of DEX is also an established catalytic inhibitor of TopoII enzyme, the use of DEX against DOX-induced cardiotoxicity lead to concern that DEX might interfere with the antitumor activity of DOX. Therefore, there is a need for new agents that can be used safely against the cardiotoxicity of DOX which does not inhibit the activity of the Topo enzyme. The aim of this study was to investigate whether Silymarin (SLY) may protect against DOX induced cardiotoxicity and assess its effect on TopII enzyme activity. Forty five male Balb/c, 6-8 weeks of age, mice were randomly divided into 6 groups. The mice in group I (control group, n=5) received intraperitoneal (ip) serum physiologic (twice each week) in the first two week and last two week of the experiment, which lasted 6 weeks. The mice in group II (group DOX, n=10) received DOX (3 mg/kg, ip) (twice each week) in the first two week and last two week of the experiment. The mice in group III (group DEX, n=5) received DEX (30 mg/kg, ip) (twice each week) in the first two week and last two week of the experiment. The mice in group IV (group DOX + DEX, n=10) received DEX (30 mg/kg, ip) 30 mins before each DOX dose. The mice in group V (group SLY, n=5) received daily SLY (100 mg/kg, by oral gavage) for 6 weeks. The mice in group VI (group DOX + SLY, n=10) received daily SLY (100 mg/kg, by oral gavage) for 6 weeks and they also received DOX (3 mg/kg, ip) (twice each week) in the first two week and last two week of the experiment. Histological examination of the myocardium from the DOX group showed diffuse myocardial damage spread throughout the LV free wall and interventricular septum. The most prominent histopathological changes in affected cardiomyocytes are cytoplasmic vacuolization in cardiomyocytes, hyaline degeneration and necrosis and myocytolysis. Heart tissue sections stained with TnI and TnT antibodies revealed that DOX led to a significant reduction in the percentage of both TnI and TnT immunoreactivity (p˂0,001). It has been noted that the administration of DEX and SLY resulted in a reduction in Tn loss (p˂0,001). A significant increase in the percentage of γH2AX expression was detected in the DOX-treated group compared to the control (p˂0,001). SLY and DEX treatment led to a significant reduction in the percentage of γH2AX expression (p˂0,001). When the experimental groups were compared each other in terms of the expression of TopIIβ, it was determined that DEX and SYL administrations caused a significant reduction in the levels of TopIIβ expression in the heart tissue samples. However, TopIIβ expression was lower in group DEX than that of group SYL. The results indicate that SYL shows protective effects on DOX-induced cardiotoxicity by decreasing TopIIβ gene expression in cardiomyocytes.