Functional role of Indomethacin Derivations For the treatment of Hepatocellular Carcinoma Priyanka Nanavati

Abstract

Aim and objective: Hepatocellular carcinoma (HCC) is primary malignancy of parenchymal cells of the liver and it is the third leading cause of cancer death globally. Several studies suggest that NSAIDs has potential to reduce cancer cell growth and cell viability, vasculogenesis, and invasiveness. Therefore, objective of our study was pharmacological evaluation of Indomethacin derivatives for treatment of hepatocellular carcinoma. Materials & Methods: The molecular docking of Indomethacin derivatives was carried out for prediction of inhibitory effect on PDGFR-α using pass online software, followed by cytotoxicity study by performing MTT assay. The selection of compound for the study was based on the IC50 values of in-vitro study. Induction of the disease was carried out with N-Nitrosodiethylamine (200 mg/kg) followed by 2-acetlyaminofluorene orally for two weeks. After 12 weeks of induction, 15 days treatment was given and blood was collected for determination of biochemical parameters and tumor markers. At the end animals were sacrificed and liver samples were isolated and morphological parameters, immunohistochemistry and histopathology was performed. Gene expression studies for VEGF was carried out. Results: All these compounds has been computationally predicted for inhibitory effect on PDGFRα and JI-MT has shown maximum inhibitory activity for PDGFRα.Compound also showed good cytotoxic effect in HepG2 cell line. In morphological evaluation, we have found statistically (p<0.05) significant reduction in number of nodules and liver weight to body weight ratio with treatment with JI-MT. Hepatoprotective role of JI-MT has been observed in tumor specific markers like α-feto protein levels, Carcinoembryonic antigen levels. The JI-MT also has shown reduction in PDGF-α levels. In our study liver markers like(ALT, ALP, AST, LDH) and total bilirubin levels were raised in the disease control group and marked decrease was observed with treatments. On histopathological examination protective effect of JI-MT was clearly visible. It has also showed increased expression of P53 in immunohistochemiscal analysis compared to disease control group. In gene expression study, we found that in disease control VEGF gene is upregulated and treatment group has shown decreased expression. Conclusion: From the present study we can conclude that JI-MT have potential in treatment of HCC by the virtue of PDGFRα inhibitory activity. Keywords : Hepatocellular carcinoma, Indomethacin derivatives, COX-2 inhibitors, PDGFR-α activity.