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

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.

Sorafenib and Mesenchymal Stem Cell Therapy: A Promising Approach for Treatment of HCC

“…Available cancer therapies such as chemotherapy, liver transplantation, surgical resection, radiofrequency ablation, immunotherapy, and hormone therapy have different response rates and efficacies due to the vast heterogeneity of HCC [26,27]. Sorafenib is an approved molecularly targeted therapy that is administered for treatment of patients with advanced HCC through its antiproliferative, antiangiogenic, and proapoptotic functions.…”

Mass spectral analysis of the multikinase inhibitor BZG and its metabolites and analysis of their binding to vascular endothelial growth factor receptor-2

“…BZG also inhibited in vitro proliferation of a panel of human cancer cells [ 7 ]. Moreover, our previous research indicated that BZG significantly inhibited Huh-7 cell derived tumor xenografts in Balb/c nude mice [ 7 , 8 ]. Studies showed relatively high concentrations of BZG in the liver and kidney providing a pharmacokinetic (PK) basis for their effective use in hepatic and renal carcinomas [ 9 ].…”