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.
Highlights
Osteosarcoma is the most common bone malignancy, accounting for about 60% of malignant bone tumors diagnosed in the children and adolescents with an aggressive local pattern of growth and high metastatic potential [1,2]
This study investigated whether 4-MD can mediate its anti-proliferative and apoptotic effects in human osteosarcoma cells through the suppression of the JAK2/signal transducers and activators of transcription 3 (STAT3) pathway
As a part of our ongoing effort for the identification of natural products with anti-cancer effects in vitro and in vivo, we present here first time that 4-MD inhibits the growth and induces apoptosis of osteosarcoma cells through the suppression of the JAK2/STAT3 pathway, and inhibits growth of osteosarcoma cells in a xenograft mouse model
Summary
Osteosarcoma is the most common bone malignancy, accounting for about 60% of malignant bone tumors diagnosed in the children and adolescents with an aggressive local pattern of growth and high metastatic potential [1,2]. The JAK2/STAT3 pathway has shown to have roles in the oncogenesis of several cell types [8-. JAK2/STAT3 signaling has been shown to regulate the expression of genes that participate in oncogenesis such as apoptosis inhibitors (Bcl-xl, Bcl-2, and Survivin) and cell cycle regulators [10]. Previous studies have reported that D. odorifera possesses a variety of beneficial properties including antioxidant, antimicrobial, antiinflammatory, and antitumor activities in diverse cells types [12,13,14,15,16,17]. We isolated and identified 4-methoxydalbergione (4-MD) from the heartwood of D. odorifera, its pharmacological effects in osteosarcoma have not been reported yet. This study investigated whether 4-MD can mediate its anti-proliferative and apoptotic effects in human osteosarcoma cells through the suppression of the JAK2/STAT3 pathway. The effects of the 4-MD in vivo xenograft models of osteosarcoma were assessed
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