Abstract
The present study was designed to evaluate the antitumor effects of the synthetic Mannich base 1,3-bis-((3-hydroxynaphthalen-2-yl)phenylmethyl)urea (1,3-BPMU) against HEP-G2 hepatoma cells and diethylnitrosamine (DEN)-induced hepatocarcinoma (HCC) in albino rats. In vitro analysis results revealed that 1,3-BPMU showed significant cytotoxicity and cell growth inhibition in HEP-G2 hepatoma cells in a concentration-dependent manner. Furthermore, flow cytometry results indicated that 1,3-BPMU enhanced early and late apoptosis. The maximum apoptosis was exhibited at a concentration of 100 μg/mL of 1,3-BPMU. In in vivo analysis, DEN treatment increased the content of nucleic acids, LPO and the activities of AST, ALT, ALP, LDH, γGT and 5’NT with decreased antioxidant activity as compared to control rats. However, 1,3-BPMU treatment to DEN-induced rats decreased the content of nucleic acids, LPO and the activities of AST, ALT, ALP, LDH, γGT and 5’NT and increased the activities of SOD, CAT, GPx, GST and GR (p < 0.05). Furthermore, 1,3-BPMU enhanced the apoptosis via upregulation of caspase-3 and caspase-9 and the downregulation of Bcl-2 and Bcl-XL mRNA expression as compared to DEN-induced rats. Histological and ultrastructural investigation showed that 1,3-BPMU treatment renovated the internal architecture of the liver in DEN-induced rats. In this study, the molecular and pre-clinical results obtained by treatment of DEN-induced rats with 1,3-BPMU suggested that 1,3-BPMU might be considered as an antitumor compound in the future.
Highlights
Hepatocellular carcinoma (HCC) is a primary liver cancer, the sixth most common malignant neoplasm, and 85% of HCC patients die in developing countries [1,2]
HEP-G2 hepatoma cells were incubated with different concentrations of 1,3-BPMU (0.001, 0.01, 0.1, 0.2. 0.5, 1, 2, 5, 10, 20, 50 and 100 μg/mL) for 0.5, 1, 1.5, 2 and 3 days at 37 ̋ C (p < 0.05)
The results showed that 1,3-BPMU treatment significantly reduced the HEP-G2 cell viability in a time- and dose-dependent manner
Summary
Hepatocellular carcinoma (HCC) is a primary liver cancer, the sixth most common malignant neoplasm, and 85% of HCC patients die in developing countries [1,2]. To trigger malignancy in different sites of the liver, numerous chemical carcinogen responses, which lead to varied patterns of cellular proliferation, occur in the development of HCC [5]. Diethylnitrosamine, known as N-nitrosodiethylamine (DEN), is extensively used as a carcinogen in the animal model. DEN is absorbed and metabolized by the pericentral zone and gets activated in the liver lobules. More activation leads to stimulated oxidative stress-mediated hepatocarcinogenesis through DNA damage by free radical formation, downregulated apoptotic genes and proteins, upregulated anti-apoptotic gene expression and protein synthesis [7]
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