Chemoprotective of Nimbolide Against Diethylnitrosamine Induced Hepatic Cancer via Alteration of NF‐κB and PI3K/Akt/mTOR Signaling Pathways

Hepatocellular carcinoma (HCC) is the 5th rank among all types of cancers, the incidence of the HCC increases globally. The current study was scrutinized the chemoprotective effect of nimbolide against dimethylnitrosamine (DEN) induced HCC in rats via alteration of PI3K/Akt/mTOR signaling pathways. Intraperitoneal administration of DEN (200 mg/kg) was used for the induction of HCC in the rats and rats were received the oral administration of nimbolide (10, 20, and 40 mg/kg). The body weight, liver weight, liver index, electrolyte, membrane bound enzymes, antioxidant, inflammatory cytokines, inflammatory parameters and apoptosis parameters were estimated. The mRNA expressions were estimated in the hepatic tissue. Nimbolide treatment improved the body weight and diminished the liver weight and liver index. Nimbolide treatment altered the electrolyte (sodium, potassium, calcium, magnesium), membrane bound enzymes, antioxidant parameters cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-10 (IL-10), interleukin-17 (IL-17), interleukin-18 (IL-18)), inflammatory parameters (cyclooxygenase-2 (COX-2), prostaglandin (PGE2), inducible nitric oxide synthetase (iNOS), nuclear factor kappa B (NF-κB), vascular endothelial growth factor (VEGF)), apoptosis parameters such as B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), Bcl-2:Bax ratio, cysteine-aspartic acid protease-3 (caspase-3) and C-reactive protein (CRP) level. Nimbolide treatment significantly (p < 0.001) altered the mRNA expression of tumor protein p53 (p53), Bax, Mechanistic target of rapamycin (mTOR), Bcl-2, Cysteine-aspartic acid protease-9 (caspase-9), caspase-3, phosphoinositide 3-kinase (PI3K), IQ motif-containing GTPase-activating protein 1 (IQGAP1), Protein kinase B (PKB) (AKT), IQ motif-containing GTPase-activating protein 2 (IQGAP2), IQ motif-containing GTPase-activating protein 3 (IQGAP3), Kirsten rat sarcoma viral oncogene homolog (KRAS) and Harvey rat sarcoma viral oncogene homolog (HRAS). The result clearly showed the chemoprotective effect of nimbolide against DEN induced HCC in rats via alteration of PI3K/Akt/mTOR signaling pathways.