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Updated: Jul 11, 2026
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Vector-based Ape1 small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo
Dong Wang1, Zhao-Yang Zhong, Meng-Xia Li
1Cancer Center, and Department of Pathology, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China. dongwang64@hotmail.com
Abstract:
Osteosarcoma is a highly vascular and extremely destructive malignancy, and the survival of patients with osteosarcoma has not improved significantly in recent years. Antiangiogenic therapy currently holds great potential in conjunction with conventional treatment modalities for osteosarcoma. However, there are examples of gradual loss of response, and perhaps acquired resistance to antiangiogenic drugs. The acquired resistance of antiangiogenesis may be associated with a lot of hypoxia-response genes. The human apurinic/apyrimidinic endonuclease (Ape1) protein, a bifunctional redox factor and apurinic/apyrimidinic (AP) endonuclease, plays a crucial role in protecting against cell death due to hypoxia. We therefore hypothesized that Ape1 may contribute to the resistance of antiangiogenic therapy. To investigate the effect of Ape1 on the sensitivity of human osteosarcoma cells to endostatin, we constructed an Ape1 small interfering RNA expression vector, pSilenceApe1. Transfection of human osteosarcoma 9901 and HOS cells with pSilenceApe1 resulted in a dose-dependent loss of Ape1 protein. pSilenceApe1 also significantly suppressed the expression of vascular endothelial growth factor (VEGF) protein in the 9901 cells. Combined treatment with pSilenceApe1 and recombinant human endostatin (rhES) showed potent antiangiogenic effects in the transwell chamber invasion assay. Then, 20 nude mice bearing 9901 xenografts were divided into four groups: the phosphate-buffered saline treatment control group; the rhES treatment group (1.5 mg/kg, daily); the pSilenceApe1 treatment group (20 microg, once every 3 days); and the combination of rhES and pSilenceApe1 treatment group. pSilenceApe1 significantly suppressed the expression of Ape1 and VEGF protein in the 9901 xenografts. The tumor-inhibition rate of the pSilenceApe1, rhES, and combination of rhES and pSilenceApe1 treatment groups was 38.23, 35.29, and 62.18%, respectively. Furthermore, a significant decrease in microvessel density with an increase in apoptosis was observed following combined treatment with pSilenceApe1 and rhES, compared with control and either agent alone in 9901 xenografts. These results indicate that Ape1 small interfering RNA could enhance the sensitivity of osteosarcoma cells to endostatin.
Insights
Targeting human apurinic/apyrimidinic endonuclease (Ape1) with small interfering RNA enhances osteosarcoma sensitivity to antiangiogenic therapy. This approach, combined with endostatin, significantly inhibits tumor growth and reduces microvessel density.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma is a destructive malignancy with limited therapeutic advancements.
- Antiangiogenic therapy shows promise but faces challenges with acquired resistance.
- Hypoxia-response genes, like Ape1, may contribute to resistance against antiangiogenic drugs.
Purpose of the Study:
- To investigate the role of human apurinic/apyrimidinic endonuclease (Ape1) in osteosarcoma resistance to antiangiogenic therapy.
- To evaluate the efficacy of targeting Ape1 in combination with endostatin for osteosarcoma treatment.
Main Methods:
- Constructed Ape1 small interfering RNA (siRNA) expression vector (pSilenceApe1).
- Transfected human osteosarcoma cells (9901 and HOS) with pSilenceApe1 to assess Ape1 and VEGF protein expression.
- Evaluated combined antiangiogenic effects of pSilenceApe1 and recombinant human endostatin (rhES) in vitro and in vivo xenograft models.
- Assessed tumor growth inhibition, microvessel density, and apoptosis in mice models.
Main Results:
- pSilenceApe1 transfection reduced Ape1 and VEGF protein expression in osteosarcoma cells and xenografts.
- Combined treatment with pSilenceApe1 and rhES demonstrated potent antiangiogenic effects.
- The combination therapy achieved a 62.18% tumor inhibition rate, significantly higher than individual treatments.
- Combined treatment led to decreased microvessel density and increased apoptosis in xenografts.
Conclusions:
- Ape1 plays a role in mediating resistance to antiangiogenic therapy in osteosarcoma.
- Ape1 siRNA can enhance the sensitivity of osteosarcoma cells to endostatin.
- Targeting Ape1 in combination with antiangiogenic agents represents a potential therapeutic strategy for osteosarcoma.
