title: 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.
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.
authors.affiliation: Department of Oral and Maxillofacial Regeneration, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Kyung-Ran
authors.initials: KR
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Hyung-Mun
authors.initials: HM
authors.lastname: Yun
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea.
authors.forename: Tran-Hong
authors.initials: TH
authors.lastname: Quang
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea.
authors.forename: Hyuncheol
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Biomedical Chemistry, College of Health and Biomedical Science, Konkuk University, Chung-Ju, Korea.
authors.forename: Dong-Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Q-Schick
authors.initials: QS
authors.lastname: Auh
authors.affiliation: 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.
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C026198:4-methoxydalbergione; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: 4-methoxydalbergione; Dalbergia odorifera; JAK2/STAT3; MAPK; osteosarcoma