title: Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1α/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model.
abstract: Endothelial progenitor cells (EPCs) are important in tumor angiogenesis. Stromal cell-derived factor-1α (SDF-1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) are key in stem cell homing. Melittin, a component of bee venom, exerts antitumor activity, however, the underlying mechanisms remain to be elucidated. The present study aimed to assess the effects of melittin on EPCs and angiogenesis in a mouse model of osteosarcoma. UMR‑106 cells and EPCs were treated with various concentrations of melittin and cell viability was determined using the MTT assay. EPC adherence, migration and tube forming ability were assessed. Furthermore, SDF‑1α, AKT and extracellular signal‑regulated kinase (ERK)1/2 expression levels were detected by western blotting. Nude mice were inoculated with UMR‑106 cells to establish an osteosarcoma mouse model. The tumors were injected with melittin, and its effects were assessed by immunohistochemistry and immunofluorescence. Melittin decreased the viability of UMR‑106 cells and EPCs. In addition, it decreased EPC adhesion, migration and tube formation when compared with control and SDF‑1α‑treated cells. Melittin decreased the expression of phosphorylated (p)‑AKT, p‑ERK1/2, SDF‑1α and CXCR4 in UMR‑106 cells and EPCs when compared with the control. The proportions of cluster of differentiation (CD)34/CD133 double‑positive cells were 16.4±10.4% in the control, and 7.0±4.4, 2.9±1.2 and 1.3±0.3% in tumors treated with 160, 320 and 640 µg/kg melittin per day, respectively (P<0.05). At 11 days, melittin reduced the tumor size when compared with that of the control (control, 4.8±1.3 cm3; melittin, 3.2±0.6, 2.6±0.5, and 2.0±0.2 cm3 for 160, 320 and 640 µg/kg, respectively; all P<0.05). Melittin decreased the microvessel density, and SDF‑1α and CXCR4 protein expression levels in the tumors. Melittin may decrease the effect of osteosarcoma on EPC‑mediated angiogenesis, possibly via inhibition of the SDF-1α/CXCR4 signaling pathway.
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Suyang
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Wu
authors.initials: W
authors.lastname: Rao
authors.affiliation: Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Chaowei
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China.
authors.forename: Mindong
authors.initials: M
authors.lastname: Du
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China.
authors.forename: Kaiyi
authors.initials: K
authors.lastname: He
authors.affiliation: College of Pharmacy, Guangxi Medical University, Nanning, Guangxi 530000, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ye
mesh_terms: D000818:Animals; D015415:Biomarkers; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D008555:Melitten / Q000494:pharmacology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D008555:Melitten; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases