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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 decreased angiogenic response.CD31 immuno-staining on bone marrow sections of control mice (A) or 5TGM1 injected mice, treated with the vehicle solution (B) or with MTM (C). Original magnification 10x. D Quantification of microvessel density (MVD) using the hot spot technique. MVD was decreased in MTM-treated mice compared with the group treated with the vehicle solution.
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pone-0062818-g006: MTM decreased angiogenic response.CD31 immuno-staining on bone marrow sections of control mice (A) or 5TGM1 injected mice, treated with the vehicle solution (B) or with MTM (C). Original magnification 10x. D Quantification of microvessel density (MVD) using the hot spot technique. MVD was decreased in MTM-treated mice compared with the group treated with the vehicle solution.

Mentions: Immunohistochemical staining of CD31 on BM sections of 5TGM1-inoculated mice and age- and sex-matched control mice, demonstrated an increase of the microvessel development in the 5TGM1 injected mice (p<0.001) (Figure 6). MTM treatment resulted in a decreased angiogenic response (p<0.01). Angiogenesis quantification is shown in Figure 6 D.


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 decreased angiogenic response.CD31 immuno-staining on bone marrow sections of control mice (A) or 5TGM1 injected mice, treated with the vehicle solution (B) or with MTM (C). Original magnification 10x. D Quantification of microvessel density (MVD) using the hot spot technique. MVD was decreased in MTM-treated mice compared with the group treated with the vehicle solution.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646989&req=5

pone-0062818-g006: MTM decreased angiogenic response.CD31 immuno-staining on bone marrow sections of control mice (A) or 5TGM1 injected mice, treated with the vehicle solution (B) or with MTM (C). Original magnification 10x. D Quantification of microvessel density (MVD) using the hot spot technique. MVD was decreased in MTM-treated mice compared with the group treated with the vehicle solution.
Mentions: Immunohistochemical staining of CD31 on BM sections of 5TGM1-inoculated mice and age- and sex-matched control mice, demonstrated an increase of the microvessel development in the 5TGM1 injected mice (p<0.001) (Figure 6). MTM treatment resulted in a decreased angiogenic response (p<0.01). Angiogenesis quantification is shown in Figure 6 D.

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