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Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors.

Otjacques E, Binsfeld M, Rocks N, Blacher S, Vanderkerken K, Noel A, Beguin Y, Cataldo D, Caers J - PLoS ONE (2013)

Bottom Line: In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment.The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation.These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium.

ABSTRACT
Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we evaluated its anti-myeloma effects in the syngenic 5TGM1 model in vitro as well as in vivo. In vitro, MTM inhibited DNA synthesis of 5TGM1 cells with an IC50 of 400 nM and induced an arrest in cell cycle progression at the G1/S transition point. Western-blot revealed an up-regulation of p53, p21 and p27 and an inhibition of c-Myc, while SP1 remained unaffected. In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment. The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation. These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation.

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MTM reduced the myeloma-associated neo-vascularization in vitro in a rat aortic ring assay.A Representative photomicrographs (scale 25×) of aortic rings cultured for 9 days with MCDB+DMEM, VEGF, MTM 400 nM, or with conditioned medium (CM) by cancer cells treated with MTM 0 nM, 200 nM or 400 nM. B A grid of concentric rings is automatically drawn by making successive dilations of the aortic ring boundary. Microvessel distribution is defined as the number of microvessel intersections with this grid plotted as a function of the distance from the ring. C and D represent the mean numbers of vessels depending of the distance to the ring for control (C) and MTM treatment (D). The addition of medium conditioned by treated 5TGM1 cells to the aortic ring culture increased the development of microvessels compared to the control condition (MCDB+DMEM) (p<0.01). This angiogenic response was inhibited (p<0.001) when increased concentrations of MTM (200 nM and 400 nM) were added to 5TGM1 cells before collection of conditioned medium.
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pone-0062818-g003: MTM reduced the myeloma-associated neo-vascularization in vitro in a rat aortic ring assay.A Representative photomicrographs (scale 25×) of aortic rings cultured for 9 days with MCDB+DMEM, VEGF, MTM 400 nM, or with conditioned medium (CM) by cancer cells treated with MTM 0 nM, 200 nM or 400 nM. B A grid of concentric rings is automatically drawn by making successive dilations of the aortic ring boundary. Microvessel distribution is defined as the number of microvessel intersections with this grid plotted as a function of the distance from the ring. C and D represent the mean numbers of vessels depending of the distance to the ring for control (C) and MTM treatment (D). The addition of medium conditioned by treated 5TGM1 cells to the aortic ring culture increased the development of microvessels compared to the control condition (MCDB+DMEM) (p<0.01). This angiogenic response was inhibited (p<0.001) when increased concentrations of MTM (200 nM and 400 nM) were added to 5TGM1 cells before collection of conditioned medium.

Mentions: Angiogenesis was first assessed in vitro by using the rat aortic ring assay (Figure 3A). Figure 3C and 3 D show the mean number of vessels in function of the distance to the ring. The addition of medium conditioned by untreated 5TGM1 cells to the aortic ring culture increased the development of microvessels compared to the control condition (MCDB+DMEM) (p<0.01) (Figure 3C). Direct addition of MTM in the rat aortic ring assay showed no effect on vascular outgrowth (Figure 3C), indicating that the observed effect was mediated through an effect on 5TGM1 cells. When increasing concentrations of MTM were added (200 nM or 400 nM) to 5TGM1 cells before collection of conditioned medium, this angiogenic response was inhibited (p<0.001) (Figure 3D).


Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors.

Otjacques E, Binsfeld M, Rocks N, Blacher S, Vanderkerken K, Noel A, Beguin Y, Cataldo D, Caers J - PLoS ONE (2013)

MTM reduced the myeloma-associated neo-vascularization in vitro in a rat aortic ring assay.A Representative photomicrographs (scale 25×) of aortic rings cultured for 9 days with MCDB+DMEM, VEGF, MTM 400 nM, or with conditioned medium (CM) by cancer cells treated with MTM 0 nM, 200 nM or 400 nM. B A grid of concentric rings is automatically drawn by making successive dilations of the aortic ring boundary. Microvessel distribution is defined as the number of microvessel intersections with this grid plotted as a function of the distance from the ring. C and D represent the mean numbers of vessels depending of the distance to the ring for control (C) and MTM treatment (D). The addition of medium conditioned by treated 5TGM1 cells to the aortic ring culture increased the development of microvessels compared to the control condition (MCDB+DMEM) (p<0.01). This angiogenic response was inhibited (p<0.001) when increased concentrations of MTM (200 nM and 400 nM) were added to 5TGM1 cells before collection of conditioned medium.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646989&req=5

pone-0062818-g003: MTM reduced the myeloma-associated neo-vascularization in vitro in a rat aortic ring assay.A Representative photomicrographs (scale 25×) of aortic rings cultured for 9 days with MCDB+DMEM, VEGF, MTM 400 nM, or with conditioned medium (CM) by cancer cells treated with MTM 0 nM, 200 nM or 400 nM. B A grid of concentric rings is automatically drawn by making successive dilations of the aortic ring boundary. Microvessel distribution is defined as the number of microvessel intersections with this grid plotted as a function of the distance from the ring. C and D represent the mean numbers of vessels depending of the distance to the ring for control (C) and MTM treatment (D). The addition of medium conditioned by treated 5TGM1 cells to the aortic ring culture increased the development of microvessels compared to the control condition (MCDB+DMEM) (p<0.01). This angiogenic response was inhibited (p<0.001) when increased concentrations of MTM (200 nM and 400 nM) were added to 5TGM1 cells before collection of conditioned medium.
Mentions: Angiogenesis was first assessed in vitro by using the rat aortic ring assay (Figure 3A). Figure 3C and 3 D show the mean number of vessels in function of the distance to the ring. The addition of medium conditioned by untreated 5TGM1 cells to the aortic ring culture increased the development of microvessels compared to the control condition (MCDB+DMEM) (p<0.01) (Figure 3C). Direct addition of MTM in the rat aortic ring assay showed no effect on vascular outgrowth (Figure 3C), indicating that the observed effect was mediated through an effect on 5TGM1 cells. When increasing concentrations of MTM were added (200 nM or 400 nM) to 5TGM1 cells before collection of conditioned medium, this angiogenic response was inhibited (p<0.001) (Figure 3D).

Bottom Line: In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment.The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation.These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium.

ABSTRACT
Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we evaluated its anti-myeloma effects in the syngenic 5TGM1 model in vitro as well as in vivo. In vitro, MTM inhibited DNA synthesis of 5TGM1 cells with an IC50 of 400 nM and induced an arrest in cell cycle progression at the G1/S transition point. Western-blot revealed an up-regulation of p53, p21 and p27 and an inhibition of c-Myc, while SP1 remained unaffected. In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment. The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation. These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation.

Show MeSH
Related in: MedlinePlus