title: 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: 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 U2OS 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.
authors.affiliation: Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
authors.forename: Hai-Yong
authors.initials: HY
authors.lastname: Ren
authors.affiliation: Department of Orthopedics, Second Jiaxing Hospital, Jiaxing, P.R. China.
authors.forename: Hai-Qing
authors.initials: HQ
authors.lastname: Lin
authors.affiliation: Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Mao
authors.affiliation: Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
authors.forename: Sheng-Dong
authors.initials: SD
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
authors.forename: Zhao-Ming
authors.initials: ZM
authors.lastname: Ye
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009019:Morphinans / Q000008:administration & dosage* / Q000494:pharmacology; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C576601:ARHGEF3 protein, human; D020533:Angiogenesis Inhibitors; C527276:CXCR4 protein, human; D009019:Morphinans; D019718:Receptors, CXCR4; D064067:Rho Guanine Nucleotide Exchange Factors; C009271:sinomenine