Protective Effects of Luteolin Against Cisplatin-Induced Hepatic and Renal Toxicity: Biochemical and Cellular Evidence.

Cisplatin is a widely used chemotherapeutic agent; however, its clinical utility is frequently limited by dose-dependent adverse effects, particularly hepatotoxicity and nephrotoxicity. Luteolin, a naturally occurring flavonoid abundant in various medicinal plants, exhibits well-documented antioxidant and anticancer activities. This study investigated whether Luteolin isolated from Pistacia terebinthus fruits could attenuate Cisplatin-induced organ toxicity while enhancing its antiproliferative effects. For the in vivo experiments, 48 male Swiss albino mice (9-10 weeks old, 26-30 g) were randomly assigned to eight groups (n = 6/group): control, Cisplatin, Luteolin (25, 50, or 100 mg/kg), and Cisplatin plus Luteolin (25, 50, or 100 mg/kg). Cisplatin (10 mg/kg/day, intraperitoneally) and/or Luteolin (25-100 mg/kg/day, orally) were administered for 14 consecutive days. Serum biochemical parameters, oxidative stress markers, antioxidant enzyme activities, and tissue injury-related biomarkers were evaluated in liver and kidney tissues. Cisplatin administration significantly increased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and glucose levels, whereas co-treatment with Luteolin markedly attenuated these alterations in a dose-dependent manner. In addition, Luteolin restored Cisplatin-induced disturbances in oxidative stress and antioxidant defense markers, including malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), HSP70 levels, superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) activities in liver and kidney tissues. To support the in vivo findings, in vitro antiproliferative assays were performed using Saos-2 osteosarcoma, HTB-9 bladder cancer, A549 lung cancer, and BEAS-2B normal epithelial cell lines. Cells were treated with Luteolin (5-200 µM) alone or in combination with Cisplatin IC50 concentrations for 24-48 h, and cell viability was assessed using the WST-1 assay. Co-treatment with Luteolin significantly enhanced Cisplatin-induced growth inhibition in cancer cells while exerting limited cytotoxicity in normal cells. Luteolin alone also demonstrated concentration-dependent antiproliferative activity. In conclusion, Luteolin exerted marked hepatorenal protective effects and enhanced the antiproliferative activity of Cisplatin in experimental models. These findings suggest that Luteolin may represent a promising adjunctive candidate for reducing Cisplatin-associated toxicity while improving therapeutic responsiveness.