Functional Role of Novel Indomethacin Derivatives for the Treatment of Hepatocellular Carcinoma Through Inhibition of Platelet-Derived Growth Factor

Abstract

Background: Several studies suggested anticancer potential of NSAIDs. Therefore, we aimed to evaluate novel indomethacin derivatives for the treatment of hepatocellular carcinoma.

Methods: The molecular docking of 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 disease was induced with N-Nitrosodiethylamine (200 mg/kg, i.p.) followed by 2-acetylaminofluorene orally for two weeks. After 12 weeks of induction, treatment was given for one week and blood was collected for determination of biochemical parameters and tumor markers. Liver samples were isolated for immunohistochemistry, histopathology, and gene expression study for VEGF.

Results: JI-MT has shown maximum inhibitory activity for PDGFRα in docking study also showed good cytotoxic effect in the HepG2 cell line and based on the IC₅₀ values, JI-MT was selected for in-vivo study. We have found statistically significant reduction in body weight gain, 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-fetoprotein levels, carcinoembryonic antigen and PDGF-α levels. Liver markers like ALT, ALP, AST, LDH and total bilirubin levels were found to be reduced with treatments. Also, on histopathological examination, the protective effect of JI-MT was observed. Treatment also showed increased expression of P53 in immunohistochemical analysis and up-regulation of VEGF gene by JI-MT.

Conclusion: From the present study, we can conclude that JI-MT has potential in treatment of HCC by the virtue of PDGFRα inhibitory activity.

Keywords: COX-2 inhibitors; Hepatocellular carcinoma; Indomethacin derivative; N-Nitrosodiethylamine; PDGFR-α activity; α-fetoprotein.