Effects of WD‑3 on tumor growth and the expression of integrin αvβ3 and ERK1/2 in mice bearing human gastric cancer using the 18F‑RGD PET/CT imaging system.

Abstract

Activation of the vitronectin receptor αvβ3 and the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 are critical events during tumor development and progression. The aim of the present study was to investigate the effects of WD-3, a formula used in traditional Chinese medicine, on integrin αvβ3 and ERK1/2 expression in vivo using a nude mouse-human gastric cancer xenograft model combined with non-invasive, real-time 18F-Arg-Gly-Asp (RGD) positron emission tomography (PET)/computerized tomography (CT) imaging methods. SGC-7901 human gastric cancer cells were subcutaneously injected into BALB/c nude mice. Following tumor development, animals were randomly assigned into the following 4 groups (n=6 mice/group): Control group (CG), Chinese medicine group (CMG), Western medicine group (WMG) and Chinese and Western medicine combination group (CMG + WMG). Mice in the CG and CMG received daily intragastric injections of 0.5 ml saline and 0.5 ml WD-3, respectively. Mice in the WMG received an intravenous injection of albumin-bound paclitaxel (25 mg/kg) on days 0, 2 and 4 Mice in the CMG + WMG received combination therapy of WD-3 and albumin-bound paclitaxel. Tumor growth was monitored using standard caliper technique and via PET imaging. 18F-RGD PET/CT analysis was performed on days 3, 7, 18 and 24 following drug administration. Radioactivity uptake was measured and expressed as the percentage of injected dose (ID) per tissue weight (%ID/g) and the standardized uptake value (SUV). Animals were sacrificed at 30 days following treatment and tumor weight was measured. Immunohistochemistry was used to detect the expression of phosphorylated (p)-ERK1/2 protein in tumor tissue samples. No statistically significant differences were observed in %ID/g and SUV among the various groups prior to treatment. At the end of treatment, mice in the CMG, WMG and CMG + WMG exhibited significantly reduced tumor mass when compared with mice in the CG. In addition, mice in the CMG and CMG + WMG demonstrated reduced %ID/g and SUV when compared with mice in the CG. Conversely, mice in the WMG exhibited no significant difference in %ID/g and SUV compared with the CG. Furthermore, p-ERK1/2 expression was significantly reduced in mice from all treatment groups when compared with those in the CG. The results of the present study suggest that the traditional Chinese formula WD-3 may inhibit gastric tumor growth, potentially via the downregulation of integrin αvβ3 and the inhibition of ERK1/2 phosphorylation in vivo.