Oncotarget

Research Papers:

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, Naotoshi Sugimoto, Hiroyuki Tsuchiya, Fuminori Kanaya, Michael Bouvet and Robert M. Hoffman _

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Oncotarget. 2016; 7:87031-87036. https://doi.org/10.18632/oncotarget.13497

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Abstract

Yasunori Tome1,2,3, Hiroaki Kimura1,4, Naotoshi Sugimoto5, Hiroyuki Tsuchiya4, Fuminori Kanaya3, Michael Bouvet2, Robert M. Hoffman1,2

1AntiCancer, Inc., San Diego, CA 92111, USA

2Department of Surgery, University of California, San Diego, CA 92103, USA

3Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0125 Japan

4Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, 920-8641 Japan

5Department of Physiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, 920-8641 Japan

Correspondence to:

Robert M. Hoffman, email: [email protected]

Keywords: αvβ3 integrin, echistatin, green fluorescent protein, red fluorescent protein, osteosarcoma, nude mice, orthotopic

Received: September 20, 2016     Accepted: October 27, 2016     Published: November 22, 2016

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.


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