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

Qin,Gang; Chen,Yongqiang; Li,Haidong; Xu,Suyang; Li,Yumei; Sun,Jian; Rao,Wu; Chen,Chaowei; Du,Mindong; He,Kaiyi; Ye,Yong

doi:10.3892/mmr.2016.5215

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

Authors:
- Gang Qin
- Yongqiang Chen
- Haidong Li
- Suyang Xu
- Yumei Li
- Jian Sun
- Wu Rao
- Chaowei Chen
- Mindong Du
- Kaiyi He
- Yong Ye
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Affiliations: Department of Orthopedics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China, Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China, College of Pharmacy, Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
Published online on: May 6, 2016 https://doi.org/10.3892/mmr.2016.5215
Pages: 57-68
Copyright: © Qin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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