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

Abstract

ABSTRACT 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.