The disintegrin echistatin in combination with doxorubicin targets high-metastatic human osteosarcoma overexpressing ανβ3 integrin in chick embryo and nude mouse models.

Yasunori Tome,Hiroaki Kimura,Fuminori Kanaya,Robert M Hoffman,Michael Bouvet,Hiroyuki Tsuchiya,Naotoshi Sugimoto

doi:10.18632/oncotarget.13497

Abstract

Echistatin, a cyclic RGD peptide, which is an antagonist of αvβ3 integrin (disintegrin), inhibited human osteosarcoma in the chick chorioallontoic membrane (CAM) model and tumor growth and pulmonary metastases in a nude mouse orthotopic model. A high-metastatic variant of human osteosarcoma, 143B-LM4, overexpressing αvβ3 integrin was used. Tumor angiogenesis by high-metastatic variant 143B-LM4 cells in the CAM was significantly inhibited by echistatin (P<0.05) as was overall growth. A doxorubicin (DOX)-echistatin combination inhibited orthotopic tumor growth compared to untreated control (P<0.01) or DOX alone (P<0.05) in nude mice. Tumor-bearing mice treated with the DOX-echistatin combination survived longer than those treated with DOX alone or control PBS (P<0.01 and P<0.01, respectively). Echistatin also inhibited experimental lung metastasis of 143B-LM4 cells in nude mice. These results suggest that DOX in combination with a disintegrin has potential to treat osteosarcoma and that αvβ3 integrin may be a target for osteosarcoma.

Highlights

Osteosarcoma is a highly-metastatic cancer that is often fatal after failure of first-line chemotherapy [1]
Fortyeight hr after echistatin administration, tumor-induced angiogenesis by 143B-LM4 cells in the chorioallantoic membrane (CAM) was significantly inhibited by echistatin (P < 0.05) (Figure 2A, 2B)
The efficacy of a DOX-echistatin combination in the orthotopic 143B-LM4 tumor model in nude mice was determined. 143B-LM4 cells were transplanted in the tibia of 15 nude mice, and they were allowed to grow to palpable size

Summary

Introduction

Osteosarcoma is a highly-metastatic cancer that is often fatal after failure of first-line chemotherapy [1]. We evaluated echistatin, targeting in combination with doxorubicin [4], against the 143B-LM4 cell line, in the chick embryo and in orthotopic and experimental-metastasis nude-mouse models. Efficacy of DOX-echistatin combination against 143B-LM4 in nude mice The efficacy of a DOX-echistatin combination in the orthotopic 143B-LM4 tumor model in nude mice was determined.

Results

Conclusion