Ellagic Acid Holds Promise Against Hepatocellular Carcinoma in an Experimental Model: Mechanisms of Action

Abstract

This research work was initiated to explore the efficacy of ellagic acid in mitigation of hepatocarcinogenesis in rats. Rats were distributed into 4 groups; negative control, hepatocellular carcinoma (HCC), doxorubicin and ellagic acid. Serum alpha-fetoprotein (AFP), glypican-3 (GPC-3), signal transducer and activator of transcription 3 (STAT3) and suppressors of cytokine signaling 3 (SOCS3) levels were assayed by ELISA. Immunohistochemical examination of hepatic VEGF expression was also conducted, along with histological procedures for examination of liver tissue sections. Significant elevation in serum AFP, GPC-3 and STAT3 levels with a significant drop in SOCS3 were observed in the HCC group. In contrast, the treated groups showed significant decline in serum AFP, GPC-3 and STAT3 levels and significant increase in SOCS3. Additionally, the HCC group declared mild positive immunoreaction for VEGF in hepatocytes while treatment with doxorubicin or ellagic acid was associated with a negative immunoreaction for VEGF. These results were supported by histological examination of liver tissue. The obtained findings suggested that ellagic acid may have beneficial chemopreventive role against hepatocarcinogenesis through its apoptotic, antiangiogenic and antiproliferative activities.

Keywords: Hepatocellular carcinoma; N−nitrosodiethylamine; ellagic acid; doxorubicin- rats.

Figure 1

Chemical Structure of Ellagic Acid

Figure 2

Effect of Treatment with Doxorubicin or Ellagic Acid on Serum AFP (A) and GPC-3 (B) Levels in HCC Rat Model. (a) Significant change at P>0.05 in comparison with the negative control group, (b) Significant change at P>0.05 in comparison with the HCC untreated group.

Figure 3

Effect of Treatment with Doxorubicin or Ellagic Acid on Serum STAT3 (A) and SOCS3 (B) Levels in HCC Rat Model. (a) Significant change at P>0.05 in comparison with the negative control group, (b) Significant change at P>0.05 in comparison with the HCC untreated group.

Figure 4

Immunohistochemical Examination of VEGF Expression in Liver Tissues of the Studied Groups. (A)Negative control, (B) HCC untreated, (C) HCC + Doxorubicin, (D) HCC + Ellagic acid

Figure 5

Photomicrograph of Liver Section of (A) negative control group shows normal histological structure of central vein (cv) and surrounding hepatocytes in the parenchyma. (H and E x 10), (B) HCC untreated group shows group of dysplastic hepatocytes with prominent nucleolus. (H and E x 40), (C) HCC + Doxorubicin group shows sever congestion in portal vein. (H and E x 40), (D) HCC + Ellagic acid group shows focal area of degenerated dysplastic with prominent nucleoli hepatocytes. (H and E x 40)