Therapeutic Effect of Melatonin and/or Adipose-Derived Mesenchymal Stem Cells Against Doxorubicin-Induced Renal Toxicity in Wister Rats

Abstract

Doxorubicin (DOX) is highly effective against cancer, but its use is limited due to significant toxicity, particularly in the liver and kidneys. This toxicity is primarily caused by oxidative stress, which results in biochemical, histological, and genetic abnormalities, and disrupts the body's antioxidant defenses. Adipose-derived mesenchymal stem cells (ADMSCs) show promise in cell therapy applications against DOX toxicity Similarly, melatonin supplementation has demonstrated therapeutic potential in mitigating DOX-induced liver and kidney damage by reducing oxidative stress. Understanding and harnessing these therapeutic effects could lead to improved treatments for DOXinduced organ damage. Aims: This study focused on evaluating how melatonin and adipose-derived mesenchymal stem cells (ADMSCs) could mitigate renal toxicity induced by doxorubicin (DOX), a potent anthracycline chemotherapeutic drug known for its severe side effects. The research aimed to explore whether the antioxidant properties of melatonin and the regenerative capabilities of ADMSCs could synergistically alleviate the adverse effects of DOX on renal function in Wistar rats. Methods: The study included two main groups: a control group receiving saline and a DOX group receiving six doses of doxorubicin to induce renal toxicity. Subsequently, rats from both groups were assigned to receive treatments of saline, ADMSCs, melatonin, or a combination of ADMSCs and melatonin. Rats were euthanized at different time points post-treatment, and blood and kidney tissue samples were collected. The analysis included assessment of oxidative stress biomarkers, DNA damage, gene expression profiles, histopathological changes, and cell homing in the kidney tissues. Results: DOX induces oxidative stress, inflammation, and genotoxicity in kidneys while reducing antioxidant enzyme activity. Melatonin and/or ADMSC treatments effectively mitigate these effects by decreasing oxidative stress, inflammation, and DNA damage. The protective mechanisms involve modulation of apoptosis pathways, evidenced by changes in p53 and Bcl2 expression levels, as well as assessment of double-strand breaks using the neutral comet assay, and also the improvement of the inflammatory markers IL-6 & IL- 10 evidenced by the histopathological results. Conclusion: Melatonin and ADMSCs demonstrate protective effects against DOX-induced renal toxicity, potentially enhancing chemotherapy safety by reducing renal damage. The synergistic benefits of combining melatonin and ADMSC therapy in improving chemotherapy tolerability warrant further investigation in preclinical models to optimize treatment strategies and validate efficacy before clinical application.