Oxidative DNA Damage as an Integrative Marker of Redox Dysfunction Associated with Doxorubicin-Induced Cardiotoxicity in Pediatric Leukemia

Figures

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  Figure 1. Proposed mechanism of Dox-induced oxidative stress and cardiotoxicity. Dox promotes mitochondrial dysfunction and reactive oxygen species (ROS) generation, leading to oxidative damage to DNA, proteins, and lipids, including the formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Dexrazoxane attenuates oxidative injury and mitochondrial ROS production, although residual damage may contribute to cardiac dysfunction and fibrosis.

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  Figure 2. Proposed mechanisms involved in Dox-induced cardiotoxicity and oxidative DNA damage. Dox promotes TOP2β-mediated DNA damage and mitochondrial ROS generation. Additional oxidative stress may result from NADPH oxidase activation, influenced by NCF4, and from the formation of doxorubicinol mediated by CBR3. Intracellular accumulation of Dox and doxorubicinol may be modulated by ABCC1. These pathways contribute to calcium dysregulation through SERCA2a and RyR2, leading to cardiotoxicity and oxidative DNA damage. Dexrazoxane attenuates TOP2β-mediated injury and reduces ROS production, although residual oxidative stress may persist. Red arrows indicate pathways promoting oxidative injury, whereas green arrows indicate the protective effects of dexrazoxane.

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  Figure 3. Distribution of 8-OHdG levels in cases and controls. The density plot shows the comparison of 8-OHdG levels in the case (pink color) and control (purple color) groups. The curve represents the number of patients at a given 8-OHdG level.

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  Figure 4. Bar graph showing mean 8-OHdG levels in controls and doxorubicin-treated ALL patients. Bars represent mean ± SD, and individual data points are overlaid to illustrate data distribution within each group. Doxorubicin-treated ALL patients exhibited significantly higher 8-OHdG levels compared with controls (p = 0.001).

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  Figure 5. Longitudinal changes in 8-OHdG levels during treatment and follow-up in controls, ALL patients without cardiotoxicity, and ALL patients with cardiotoxicity. Lines represent mean values and shaded regions represent variability across serial measurements. Treatment phases are indicated at the top of the figure. Patients who developed cardiotoxicity showed persistently higher 8-OHdG levels throughout follow-up, with progressive increases during reinduction and vigilance phases. Arrows indicate the timing of cardiotoxicity detection events. The table below the graph shows the number of patients available at each time point.

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  Figure 6. Violin plot with overlaid individual data points showing the distribution of 8-OHdG concentrations according to cardiotoxicity grade (mild, moderate, and severe). Each point represents a patient; the x-axis corresponds to cardiotoxicity grade and the y-axis to 8-OHdG concentration (ng/mg). Triangles represent boys and circles represent girls. The violin-shaped contours illustrate the distribution of values within each severity category.

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  Figure 7. Relationship between 8-OHdG concentration levels with total patient doses. The dots represent individual patients differentiated by sex. The y-axis shows the 8-OHdG levels for each dot, and the x-axis shows the total Dox doses.