Sinomenine prevents metastasis of human osteosarcoma cells via S phase arrest and suppression of tumor-related neovascularization and osteolysis through the CXCR4-STAT3 pathway

Abstract

Abstract. Osteosarcoma is the most common primary malignant tumor of the 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 antitumor and anti-invasion effect on various cancers. However, the effect of sinomenine on human osteosarcoma and the underlying mechanisms remains unknown. We report 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 of invasion and migration in osteosarcoma cells as well as tube formation ability in the human umbilical vein endothelial cells (HUVEC) and U 2 OS cells. Furthermore, it demonstrated that CXCR4 played a key role contributing to invasion in osteosarcoma which is considered to be a core target site in sinomenine treatment. Sinomenine inhibited invasion by suppressing CXCR4 and STAT3 phosphorylation then downregulating the expression of MMP-2, MMP-9, RANKL, VEGF downstream. In addition, 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 various comprehensive means, sinomenine inhibits metastasis in osteosarcoma. Taken together, our results revealed that sinomenine caused S phase arrest, inhibited invasion and metastasis via suppressing the CXCR4-STAT3 pathway and then osteoclastogenesis-mediated bone destruction and neovascularization in osteosarcoma. Sinomenine is therefore a promising adjuvant agent for metastasis control in osteosarcoma.

Saffron carotenoids inhibit STAT3 activation and promote apoptotic progression in IL-6-stimulated liver cancer cells

“…For example, quercetin inhibited the IL-6/STAT3 signaling pathway and inhibited growth and migration of glioblastoma cells (46). Plumbagin downregulated cyclin D1 and VEGF expression through STAT3 regulation (47), and sinomenine inhibited the invasion and metastasis through inhibition of the CXCR4-STAT3 pathway (48). As observed in these studies, crocin ameliorated the expression of genes related to cell proliferation and invasion, as evidenced by decreased expression of cyclin D1, VEGF and CXCR4.…”

Magnolol induces apoptosis in osteosarcoma cells via G0/G1 phase arrest and p53‐mediated mitochondrial pathway

“…20 Tumor metastasis involves a series of important processes including tumor cells detach from the primary site, entry into the surrounding matrix, into the circulatory or lymphatic system, adherence to the endothelial cell wall and migration to the outside of the blood vessels, and angiogenesis and form new metastases. 21 To evaluate the biological effect of magnolol on osteosarcoma cells' migration, and invasion, we carried out wound healing and transwell invasion assay in vitro. Our results have shown that the migratory capability of MG-63 and 143B cells in magnolol-treated groups was weaker than that of the control group (Figure 2A and 2B).…”

Ursolic acid inhibits proliferation and induces apoptosis by inactivating Wnt/β-catenin signaling in human osteosarcoma cells

“…Herb-derived component is becoming increasingly important in tumor therapies. For example, curcumin, sinomenine and oldenlandia were all identified to be effective anti-osteosarcoma drugs (32)(33)(34). UA was identified in wax coating of apples 100 years ago.…”