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

摘要

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.