Sinomenine Induces Apoptosis In Osteosarcoma Via Endoplasmic Reticulum Stress By ROS Generation And Inhibits Prolifenation,Invasion And Metastasis

Osteosarcoma is the most common primary malignant tumor of bone. The long-term survivals continue to be unsatisfactory for patients with metastatic and recurrent disease. Metastasis is still a severe challenge in osteosarcoma treatment. Sinomenine, an alkaloid from traditional Chinese medicine, has been proved to possess potent anti-tumor and anti-invasion effect on various cancers. However, the effect of sinomenine on human osteosarcoma and the underlying mechanisms remains unknown. We reported here that sinomenine inhibited proliferation by inducing S phase arrest and suppressing the clone formation. Significant inhibitory effects were found in invasion and metastasis in osteosarcoma, but little cytotoxicity was observed in tested concentrations. Exposure to sinomenine resulted in suppression in invasion and migration in osteosarcoma cells as well as tube formation abilities both the HUVEC and U2OS cells. Furthermore, it demonstrated that CXCR.4 played a key role contributing to invasion in osteosarcoma which considered to be a core target site in sinomenine treatment. Sinomenine inhibited invasion by suppressing CXCR4 and STAT3 phosphorylation then down-regulating the expressions of MMP-2, MMP-9, RANKL, VEGF downstream. And then RANKL-mediated bone destruction stimulated by osteoclastogenesis and VEGF-related neovascularization were restrained. Importantly, in vivo, sinomenine suppressed proliferation, osteoclastogenesis and bone destruction. Through these varieties of comprehensive means, sinomenine inhibits metastasis in osteosarcoma. Taken together, our results revealed that sinomenine caused S phase arrest, inhibited invasion and metastasis via suppressing CXCR4-STAT3 pathway and then osteoclastogenesis-mediated bone destruction and neovascularization in osteosarcoma. Sinomenine is therefore a promising adjuvant agent for metastatic control in osteosarcoma.