Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy. 
Many recent studies have shown that DOX toxicity involves generation of reactive 
oxygen species (ROS). Although protection or alleviation of DOX toxicity can be 
achieved by administration of antioxidant vitamins such as ascorbic acid and 
vitamin E, their cardioprotective effect remains controversial. Thus alternative 
naturally occurring antioxidants may potentially be candidates for antioxidant 
therapy. In this study, we investigated the antioxidative and cytoprotective 
effects of Phyllanthus urinaria (PU) against DOX toxicity using H9c2 cardiac 
myoblasts. The total antioxidant capacity of PU (1 mg/ml) was 5306.75+/-461.62 
FRAP value (microM). DOX IC50 values were used to evaluate the cytoprotective 
effects of PU ethanolic extract (1 or 10 microg/ml) in comparison with those of 
ascorbic acid (VIT C, 100 microM) and N-acetylcysteine (NAC, 100 microM). PU 
treatments (1 or 10 microg/ml) dose dependently caused rightward DOX IC50 shifts 
of 2.8- and 8.5-fold, respectively while treatments with VIT C and NAC increased 
DOX IC50 by 3.3- and 4.2-fold, respectively. Additionally, lipid peroxidation 
and caspase-3 activity were parameters used to evaluate cytoprotective effect. 
All antioxidants completely inhibited cellular lipid peroxidation and caspase-3 
activation induced by DOX (1 microM). Endogenous antioxidant defense such as 
total glutathione (tGSH), catalase and superoxide dismutase (SOD) activity was 
also modulated by the antioxidants. PU treatment alone dose dependently 
increased tGSH, and this effect was retained in the presence of DOX. Similar 
effect was observed in the assessment of catalase and SOD enzyme activity. The 
nuclear factor kappaB (NFkappaB) transcription factor assay demonstrated that 
all antioxidants significantly inhibited DOX-induced NFkappaB activation. Our 
results suggest that PU protection against DOX cardiotoxicity was mediated 
through multiple pathways and this plant may serve as an alternative source of 
antioxidants for prevention of DOX cardiotoxicity.