Effect of BZG-4000, a novel multi-targeted kinase inhibitor with potent anticancer activity, on a hepatocellular carcinoma xenograft model

Sci Rep. 2014 Mar 17:4:4324. doi: 10.1038/srep04324.

Abstract

The present study was to synthesize a novel multi-targeted kinase inhibitor and evaluated its anticancer effects on a hepatocellular carcinoma xenograft model. In our study, in vivo efficacy was determined in nude mice bearing HuH7 human HCC xenografts. The mice were randomly divided into the following five groups with the use of a randomization chart (n = 8 in each group): high-dose BZG-4000 group, medium-dose BZG-4000 group, low-dose BZG-4000 group, sorafenib group, and model group. Tumor size measurements included the length (L) and width (W) measured with calipers, and tumor volume was calculated as (LW∧2)/2. Tumor tissues slides were hematoxylin and eosin (HE) stained for histopathological examination. Immunohistochemistry detected CD31 expression, and Western blotting measured VEGF protein expression. We found that when BZG-4000 was administered orally to xenograft HuH7 nude mice, tumor growth was inhibited and significant tumor shrinkage was evident. After oral administration of BZG-4000 at 40 mg/kg/day, the tumor weight and volume were significantly lower than tumors of the sorafenib group. BZG-4000 considerably decreased the expression of CD31 and VEGF in tumors compared to tumors treated with positive control drug. It was concluded that BZG-4000 has the potential to inhibit the tumorigenesis of hepatocellular carcinoma in vivo by decreasing the expression of CD31 and VEGF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Administration Schedule
  • Gene Expression
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / pharmacology*
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Sorafenib
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • BZG-4000
  • Phenylurea Compounds
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Protein Kinase Inhibitors
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Niacinamide
  • Sorafenib