Gallium Nanoparticle-Mediated Reduction of Brain Specific Serine Protease-4 in an Experimental Metastatic Cancer Model

Abstract

Purpose:Tumor growth and metastasis depend on angiogenesis; therefore, efforts are being made to develop specific angiogenic inhibitors. Gallium (Ga) is the second most common metal ion, after platinum, used in cancer treatment. Its activities are numerous and various. In the present study, we aimed to investigate the effect of Ga on brain metastasis arising from hepatocellular carcinoma (HCC).Materials and methods:Forty experimental rats (divided into 4 groups) received diethylnitrosamine (DEN) at a dose (20 mg/kg.b.wt.; for 6 weeks) to induce HCC and were treated with Ga nanoparticles (GaNPs) with the bacterium Bacillus licheniformis (1mg/kg.b.wt.). Liver functions (alanine aminotransferase; (ALT), aspartate aminotransferase; (AST) and gamma glutamyl transferase; (GGT) and alpha-fetoprotein (AFP)) were assessed with histopathological examination of liver sections to confirm the induction of HCC. In addtion, brain-specific serine protease 4 (BSSP4), extracellular signal-regulated kinase (ERK), a microtubule-associated protein (Tau), vascular endothelial growth factor (VEGF), vascular cells adhesion molecule-1 (VCAM-1), cytochrome P450 (CYP450), lipid peroxidation (MDA) and glutathione-S-transferase (GST) were measured in brain tissue.Results:GaNPs ranged from 5 to 7 nm. HCC was confirmed by elevation in liver enzymes and AFP. Additionally, histopathological examination of liver showed focal area of anaplastic hepatocytes with other cells forming acini associated with fibroblastic cell proliferation. In brain, compared to the DEN alone group, we found that GaNPs modulated brain metastasis by reducing CYP450 and BSSP4 mRNA, and protein expression of p-ERK and p-Tau, and angiogenesis mediators (VEGF and VCAM-1). Also, GaNPs elevated lipid peroxidation and GST activity.Conclusion:It is concluded that GaNPs may prevent metastasis via inhibition of BSSP4 mRNA expression leading to suppression of a variety of growth factors and cell adhesion molecules involved in tumor growth and angiogenesis.