Cirsimaritin attenuates cisplatin-induced hepatotoxicity via modulation of oxidative stress and NF-κB/Akt signaling pathways in rats

Background and aim Cisplatin is a successful medicinal drug and an efficient chemotherapeutic agent that has a dose-dependent hepatotoxicity. The present study aimed to examine the hepatoprotective function of cirsimaritin against cisplatin-mediated liver injury and to determine whether cirsimaritin affects the antitumor activity of cisplatin.Experimental approach Adult male Wistar rats were pretreated with cirsimaritin (50 or 100 mg/kg, p.o.) for 7 days before a single i.p. injection of cisplatin (7.5 mg/kg). Biochemical, histological, oxidative, and molecular endpoints were evaluated. The anticancer activity of cisplatin alone or in combination with cirsimaritin was measured in MCF-7 breast cancer cells by MTT assay.Key findings The injection of cisplatin resulted in a marked rise in serum ALT and AST levels (p < 0.001), an increase that was significantly inhibited by cirsimaritin at 50 mg/kg (p < 0.01) and 100 mg/kg (p < 0.001). The increased serum triglycerides and total cholesterol (p < 0.001) were significantly attenuated by 100 mg/kg of cirsimaritin (p < 0.05). Hepatic malondialdehyde (MDA) and NOx (nitrate/nitrite), which were elevated by cisplatin (p < 0.001), were decreased by cirsimaritin in a dose-dependent manner (p < 0.01 and p < 0.001, respectively), whereas GSH, which was downregulated by cisplatin (p < 0.001), was upregulated by cirsimaritin (p < 0.01 for 50 mg/kg; p < 0.001 for 100 mg/kg). Histopathology confirmed cirsimaritin-mediated structural restoration. In Western blot analysis, cirsimaritin downregulated nuclear factor-κB (NF-κB) (p < 0.001) and upregulated phosphorylated Akt (p-Akt) expression (p < 0.01). In MCF-7 cells, cirsimaritin (25 and 50 µM) potentiated cisplatin-induced cytotoxicity did not antagonize cisplatin cytotoxicity.Conclusion Our findings also indicate that cirsimaritin induces dose-dependent hepatoprotection against cisplatin toxicity without decreasing its anticancer activity, thus making it a good candidate as adjuvant therapy in oncology.