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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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Related in: MedlinePlus

MTM induces decreased VEGF and IP10 secretion.Levels of VEGF were determined in medium conditioned by 5TGM1 cell following 24 h of MTM treatment. Levels of IP10 were determined in both conditioned medium and cell lysate. Results were obtained using ELISA assays.
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pone-0062818-g004: MTM induces decreased VEGF and IP10 secretion.Levels of VEGF were determined in medium conditioned by 5TGM1 cell following 24 h of MTM treatment. Levels of IP10 were determined in both conditioned medium and cell lysate. Results were obtained using ELISA assays.

Mentions: As VEGF plays a crucial role in angiogenesis, the expression of this protein was assessed by ELISA in the conditioned medium of cultured myeloma cells (Figure 4). After MTM treatment (200 nM and 400 nM), VEGF production was significantly (p<0.01) decreased. To assess the expression of other cytokines and to obtain a more global view of the effect of MTM on angiogenesis, a cytokine array was performed on the conditioned medium of treated (400 nM) and the non-treated 5TGM.1 cells (Figure S1 A and B). A down-regulation of several pro-angiogenic factors as well as an up-regulation of anti-angiogenic factors was found following MTM treatment. Notably, among the tested cytokines, serpin E1 and IP10 were both found to be up-regulated in the treated conditioned medium (Figure S1 C). In particular, the member of CXC sub-family IP10 is known to be expressed by endothelial cells and to be a potent angiogenesis inhibitor in vivo[28]. Considering its acknowledged role in angiogenesis, IP10 expression was also evaluated by ELISA in both cell lysates and conditioned medium (Figure 4). Following MTM treatment (200 nM and 400 nM, respectively), IP10 secretion was significantly induced both in 5TGM.1 cell lysates (p<0.01 for both concentrations) and conditioned medium (p<0.01 for 200 nM; p<0.001 for 400 nM).


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 induces decreased VEGF and IP10 secretion.Levels of VEGF were determined in medium conditioned by 5TGM1 cell following 24 h of MTM treatment. Levels of IP10 were determined in both conditioned medium and cell lysate. Results were obtained using ELISA assays.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062818-g004: MTM induces decreased VEGF and IP10 secretion.Levels of VEGF were determined in medium conditioned by 5TGM1 cell following 24 h of MTM treatment. Levels of IP10 were determined in both conditioned medium and cell lysate. Results were obtained using ELISA assays.
Mentions: As VEGF plays a crucial role in angiogenesis, the expression of this protein was assessed by ELISA in the conditioned medium of cultured myeloma cells (Figure 4). After MTM treatment (200 nM and 400 nM), VEGF production was significantly (p<0.01) decreased. To assess the expression of other cytokines and to obtain a more global view of the effect of MTM on angiogenesis, a cytokine array was performed on the conditioned medium of treated (400 nM) and the non-treated 5TGM.1 cells (Figure S1 A and B). A down-regulation of several pro-angiogenic factors as well as an up-regulation of anti-angiogenic factors was found following MTM treatment. Notably, among the tested cytokines, serpin E1 and IP10 were both found to be up-regulated in the treated conditioned medium (Figure S1 C). In particular, the member of CXC sub-family IP10 is known to be expressed by endothelial cells and to be a potent angiogenesis inhibitor in vivo[28]. Considering its acknowledged role in angiogenesis, IP10 expression was also evaluated by ELISA in both cell lysates and conditioned medium (Figure 4). Following MTM treatment (200 nM and 400 nM, respectively), IP10 secretion was significantly induced both in 5TGM.1 cell lysates (p<0.01 for both concentrations) and conditioned medium (p<0.01 for 200 nM; p<0.001 for 400 nM).

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