Efficacy of pEgr-1-endostatin combined with ionizing radiation on hypoxic conditions in nude mice bearing SKOV3 ovarian carcinoma

摘要

Hypoxia occurs in a wide range of solid tumors, and is strongly associated with radio-resistance of malignant tumors. The aim of the present study was to investigate the effect of endostatin combined with ionizing radiation (IR) on hypoxic conditions. A total of 24mice bearing SKOV3 ovarian carcinoma were divided into three groups. Following injection with pEgr-1-endostatin plasmid for 12h, the mice in the endostatin-IR-treated group were exposed to 300cGy/min X-ray for 48h, and the IR-treated group was exposed to the same condition. Then, the expression of endostatin, hypoxia-inducible factor (HIF)-1 alpha and vascular endothelial growth factor (VEGF) was detected by reverse transcription-polymerase chain reaction, ELISA, immunohistochemistry and western blotting. In addition, the tumor microvessel density (MVD) was examined by immunohistochemistry analysis of cluster of differentiation31-positive cells. The results revealed that pEgr-1-endostatin was successfully induced by IR. The level of endostatin messenger RNA in the endostatin-IR-treated group was significantly higher than that in the control and IR-treated groups (F= 380.078, P< 0.001). Statistical differences were also examined at the protein level by western blotting and ELISA. An obvious increase in MVD was observed in the IR-treated group compared with that in the control group (t= 7.040, P< 0.001), and a significant decrease in MVD was observed in the endostatin-IR-treated group compared with that in the control group (t= 18.153, P< 0.001). By comparing the morphology of the tumor vasculature in the three it was noticed that the microvessels in the endostatin-IR-treated group were more regularly distributed and had fewer giant branches than those in the IR-treated group. Further investigation revealed that the expression levels of HIF-1 alpha and VEGF in the endostatin-IR-treated group were lower compared with those in the control (t= 5.339, P= 0.001; and t= 13.880, P< 0.001, respectively) and the IR-treated groups (t= 12.930, P< 0.001; and t= 14.050, P< 0.001, respectively). Our findings suggested that endostatin decreased the number of microvessels via the HIF-1/VEGF signaling pathway, and that pEgr-1-endostatin combined with IR may improve hypoxic conditions and may be a novel approach for treating solid tumors.