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Fig. 6 | Journal of Experimental & Clinical Cancer Research

Fig. 6

From: The HIF1α-PDGFD-PDGFRα axis controls glioblastoma growth at normoxia/mild-hypoxia and confers sensitivity to targeted therapy by echinomycin

Fig. 6

Echinomycin blocks HIF1α-PDGFD-PDGFRα autocrine/feedforward pathway and blunts AKT activation, leading to the apoptosis of GBM cells and the retardation of implanted tumors. A,B,C,D Echinomycin blocks HIF1α accumulation and AKT activation and the expression of PDGFRα and PDGF-D. U251 cells (A, B, D) or primary Glio-1 cells (C) were treated with Echinomycin at different dosages and times as indicated, at normoxia or mild hypoxia (A). Indicated protein levels were detected by Western blot. E Echinomycin inhibits the release of PDGF-D from U251 cells. The cells were treated with Echinomycin for 24 h before detecting PDGF-DD levels released in the treated medium. F Echinomycin induced apoptosis of U251 cells. Annexin V staining was performed on U251 cells that were treated for 48 h with different dosages of Echinomycin. The average percentage of apoptotic cells from three independent experiments was readout by flow cytometry. G, H Liposomal echinomycin (LEM) improves the survival of primary Glio-1 or Glio-2 bearing NSG mice. Kaplan-Meier survival curves are shown for the recipient mice treated with LEM or vehicle as described in methods. Data shown are representative of three independent experiments. I Histological staining of Glio-1 mice. NSG mice bearing Glio-1 tumors were treated with vehicle or LEM as described in methods and perfused for histological staining on day 50. Serial sections were cut for brain tissues spanning the tumor site as diagramed in I, top left. I, top right depicts the H&E stained sections of vehicle or LEM treated mice through each of three serial cuts (numbered 1–3) indicated in the diagram. Immunofluorescence staining depicts the co-staining of cleaved caspase 3 and Ki67 (I, lower). The letter T marks the region of GBM tumor, with white line marking the boundary between tumor and adjacent normal brain tissue. J Immunofluorescence staining of Glio-1 mice as in I, showing co-staining for HIF1α and PDGF-D

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