Nimbolide inhibits tumor growth by restoring hepatic tight junction protein expression and reduced inflammation in an experimental hepatocarcinogenesis

Figure 8 Schematic representation of the mechanism of action of nimbolide in diethylnitrosamine and N-nitrosomorpholine induced hepatocellular carcinoma mice. Nimbolide treatment inhibits tumor growth in diethylnitrosamine and N-nitrosomorpholine induced Hepatocellular carcinoma (HCC) mice by targeting tight junctions (TJs) proteins [Zonula occludens-1 (ZO-1) and Occludin]. Nimbolide mediated up-regulation of ZO-1 represses the transcriptional activity of ZO-1 associated nucleic acid binding protein at a junctional site preventing its nuclear accumulation and thus preventing the induction of cell cycle related genes cyclin dependent kinase 4, cyclinD1 and proliferating cell nuclear antigen. Nimbolide treatment also restores barrier integrity by up-regulation TJs proteins which prevent translocation of growth factors and nutrients necessary for cell growth from apical to the basolateral domain. Further, nimbolide also targets the nuclear factor of kappa light polypeptide gene enhancer in B-cells pathway ameliorating inflammation in HCC mice. ZO-1: Zonula occludens 1; ZONAB: ZO-1 associated nucleic acid binding protein; CDK4: Cyclin dependent kinase; PCNA: Proliferating cell nuclear antigen; NF-κB: Nuclear factor of kappa light polypeptide gene enhancer in B-cells; IL-1β: Interleukin 1 beta; TNF-α: Tumor necrosis factor alpha; HCC: Hepatocellular carcinoma.