article · Frontiers in Pharmacology
Doxorubicin is an effective chemotherapy treatment, but kidney toxicity frequently restricts its therapeutic utility. This study evaluated whether two incretin-based diabetes medications, semaglutide and alogliptin, could protect against doxorubicin-induced kidney damage in adult male rats. Animals treated with doxorubicin received either oral alogliptin or subcutaneous semaglutide across ten days alongside control groups. Both therapies significantly improved kidney function, as shown by lower serum levels of creatinine, urea, and cystatin C compared to doxorubicin alone. Furthermore, both drugs mitigated oxidative stress by lowering malondialdehyde levels and elevating antioxidant defences including glutathione and superoxide dismutase. Co-treatment with either agent also reversed doxorubicin-induced reductions in renal SIRT1 and Nrf2 expression while dampening the inflammatory markers NF-κB and TNF-α. Both incretin-based pathways showed equally positive renoprotective effects.
Chemotherapy drugs such as doxorubicin save lives, but their toxic side effects on vital organs like the kidneys can limit treatment doses and harm patient outcomes. Demonstrating that existing incretin-based therapies can protect kidney tissue offers an encouraging avenue for drug repurposing, which could eventually help cancer patients tolerate essential chemotherapy treatments with fewer toxic complications.
This research suggests a potential drug repurposing opportunity for pharmaceutical developers and oncology clinicians seeking supportive therapies to counter chemotherapy-induced organ damage. However, the work remains at an early stage of preclinical animal research. Extensive further testing, including safety evaluations in tumour-bearing models and human clinical trials, will be required to confirm whether these existing diabetes treatments can be safely combined with doxorubicin in practice.
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<b>Introduction:</b> Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms. <b>Methods:</b> Adult male rats were divided into six groups: control (received the vehicle), DOX (20 mg/kg, single I.P. on day 8), DOX + ALO (20 mg/kg/day, P.O. for 10 days), DOX + SEM (12 μg/kg/day, S.C. for 10 days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations. <b>Results:</b> The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO- or SEM-treated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM. <b>Discussion:</b> Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy.
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DOI: 10.3389/fphar.2024.1353029
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