Oncotarget

Research Papers:

4-Methoxydalbergione suppresses growth and induces apoptosis in human osteosarcoma cells in vitro and in vivo xenograft model through down-regulation of the JAK2/STAT3 pathway

Kyung-Ran Park, Hyung-Mun Yun, Tran-Hong Quang, Hyuncheol Oh, Dong-Sung Lee, Q-Schick Auh and Eun-Cheol Kim _

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Oncotarget. 2016; 7:6960-6971. https://doi.org/10.18632/oncotarget.6873

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Abstract

Kyung-Ran Park1,*, Hyung-Mun Yun2,*, Tran-Hong Quang3, Hyuncheol Oh3, Dong-Sung Lee4, Q-Schick Auh5 and Eun-Cheol Kim2

1 Department of Oral and Maxillofacial Regeneration, Kyung Hee University, Seoul, Republic of Korea

2 Department of Oral and Maxillofacial Pathology, School of Dentistry and Research Center for Tooth and Periodontal Regeneration (MRC), Kyung Hee University, Seoul, Republic of Korea

3 Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea

4 Department of Biomedical Chemistry, College of Health and Biomedical Science, Konkuk University, Chung-Ju, Korea

5 Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea

* These authors have contributed equally to this work as first authors

Correspondence to:

Eun-Cheol Kim, email:

Keywords: Dalbergia odorifera, 4-methoxydalbergione, osteosarcoma, JAK2/STAT3, MAPK

Received: August 12, 2015 Accepted: January 03, 2016 Published: January 09, 2016

Abstract

Although the heartwood of Dalbergia odorifera T. Chen (Leguminosae) is an important source of traditional Korean and Chinese medicines, the effects of novel compound methoxydalbergione (4-MD) isolated from Dalbergia odorifera was not reported. Herein, we investigated the effects of the 4-MD in vitro and in vivo against osteosarcoma cells and its molecular mechanisms. 4-MD inhibited the proliferation of osteosarcoma cells and induced apoptosis as evidenced by Annexin V + and TUNEL + cells. This apoptosis was accompanied by upregulation of apoptotic proteins (procaspase-3 and PARP), but downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Survivin). 4-MD inhibited phosphorylation of JAK2 and STAT3 with the inactivation of mitogen-activated protein kinases (MAPKs) and CREB, and the upregulation of PTEN in osteosarcoma cells. Importantly, 4-MD reduced colony formation in soft agar and inhibited tumor growth in mice xenograft model in association with the reduced expression of PCNA, Ki67, p-STAT3, and Survivin. Taken together, the present study for the first time demonstrates that 4-MD exerts in vitro and in vivo anti-proliferative effects against osteosarcoma cells through the inhibition of the JAK2/STAT3 pathway, and suggest the potential for therapeutic application of 4-MD in the treatment of osteosarcoma.


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