Potential Therapeutic Effect of Sinigrin on Diethylnitrosamine-Induced Liver Cancer in Mice: Exploring the Involvement of Nrf-2/HO-1, PI3K–Akt–mTOR Signaling Pathways, and Apoptosis

Sinigrin is a glucosinolate present in plants of the family Brassicaceae and has been considered for its anticancer potential. This study examines the efficacy of sinigrin on the liver cancer caused by diethylnitrosamine (DEN) in mice through the analysis of its impact on the Nrf-2/HO-1, PI3K-Akt-mTOR, and apoptotic pathways. Development of liver cancer was induced by intraperitoneal injection at the age of 14 days with DEN (25 mg/kg) in mice. Thereafter, sinigrin was orally administered at doses of 10 and 20 mg/kg body weight per day the last 28 days. At the end of 10 weeks, mice were sacrificed and then we conducted hepatic biochemical and molecular assessments. Sinigrin reduced the serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and bilirubin but increased total protein, and albumin, levels. Sinigrin increased the antioxidant enzymes (SOD, CAT, GPx, and GST) as indicated by reduced 8-OHdG, TBARS and increased glutathione. Sinigrin reduced the levels of inflammatory cytokines (IL-6, IL-1β, TNF-α, and NF-κB p65) and PI3K/AKT/mTOR signaling pathway. Sinigrin also activated the intrinsic mitochondrial apoptosis pathway mediated by p53, downregulated antiapoptotic proteins (Bcl-2), up-regulated pro-apoptosis regulatory proteins like Bax and caspase-3. All these results indicate that the protective effects of sinigrin against liver cancer are likely to be applied as an effective therapeutic agent through its antioxidant and pro-apoptotic activities.