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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 BM colonisation by 5TGM1 (A) and splenomegaly (B).Tumour load was assessed by flow cytometry analysis of GFP cells and spleen weight was measured. Starting the day after injection (day 1), a group of mice was treated intraperitonealy twice weekly with MTM or vehicle (DMSO dissolved in PBS). At day 32, mice were sacrificed.
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pone-0062818-g005: MTM reduced BM colonisation by 5TGM1 (A) and splenomegaly (B).Tumour load was assessed by flow cytometry analysis of GFP cells and spleen weight was measured. Starting the day after injection (day 1), a group of mice was treated intraperitonealy twice weekly with MTM or vehicle (DMSO dissolved in PBS). At day 32, mice were sacrificed.

Mentions: Intraperitoneal treatment with MTM was well tolerated and did not induce any weight loss (results not shown). The treatment of mice with MTM decreased BM infiltration by 5TGM1 cells with 25% compared to vehicle treated 5TGM1 mice (p<0.05) (Figure 5 A). Splenomegaly was also significantly reduced by 21% after chronic treatment of animals with MTM compared to treatment with vehicle (p<0.05) (Figure 5 B).


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 BM colonisation by 5TGM1 (A) and splenomegaly (B).Tumour load was assessed by flow cytometry analysis of GFP cells and spleen weight was measured. Starting the day after injection (day 1), a group of mice was treated intraperitonealy twice weekly with MTM or vehicle (DMSO dissolved in PBS). At day 32, mice were sacrificed.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062818-g005: MTM reduced BM colonisation by 5TGM1 (A) and splenomegaly (B).Tumour load was assessed by flow cytometry analysis of GFP cells and spleen weight was measured. Starting the day after injection (day 1), a group of mice was treated intraperitonealy twice weekly with MTM or vehicle (DMSO dissolved in PBS). At day 32, mice were sacrificed.
Mentions: Intraperitoneal treatment with MTM was well tolerated and did not induce any weight loss (results not shown). The treatment of mice with MTM decreased BM infiltration by 5TGM1 cells with 25% compared to vehicle treated 5TGM1 mice (p<0.05) (Figure 5 A). Splenomegaly was also significantly reduced by 21% after chronic treatment of animals with MTM compared to treatment with vehicle (p<0.05) (Figure 5 B).

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