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In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy.

Craveiro RB, Ehrhardt M, Holst MI, Pietsch T, Dilloo D - Oncotarget (2014)

Bottom Line: Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival.Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib.Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany. These authors contributed equally to this work.

ABSTRACT
Regardless of the recent advances in cytotoxic therapies, 30% of children diagnosed with medulloblastoma. succumb to the disease. Therefore, novel therapeutic approaches are warranted. Here we demonstrate that Pazopanib a clinically approved multi-kinase angiogenesis inhibitor (MKI) inhibits proliferation and apoptosis in medulloblastoma cell lines. Moreover, Pazopanib profoundly attenuates medulloblastoma cell migration, a prerequisite for tumor invasion and metastasis. In keeping with the observed anti-neoplastic activity of Pazopanib, we also delineate reduced phosphorylation of the STAT3 protein, a key regulator of medulloblastoma proliferation and cell survival. Finally, we document profound in vivo activity of Pazopanib in an orthotopic mouse model of the most aggressive c-myc amplified human medulloblastoma variant. Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival. Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib. Both compounds share a similar target profile but display different pharmacodynamics and pharmacokinetics with distinct cytotoxic activity in different tumor entities. Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.

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Related in: MedlinePlus

The anti-proliferative and pro-apoptotic effects of Pazopanib and Sorafenib are associated with a reduction of STAT3 phosphorylation at tyrosine 705In Daoy, MEB-Med-8A, D283 Med and D341 Med cells were treated with Pazopanib and Sorafenib at concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM) for a 1, 12, 24 and 48h period. Total protein levels and the phosphorylation status of STAT3 were determined by westernblot. Beta-tubulin and ERGIC53 respectively served as loading controls. The data-set shown represents 1 of 3 independent experiments.
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Figure 5: The anti-proliferative and pro-apoptotic effects of Pazopanib and Sorafenib are associated with a reduction of STAT3 phosphorylation at tyrosine 705In Daoy, MEB-Med-8A, D283 Med and D341 Med cells were treated with Pazopanib and Sorafenib at concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM) for a 1, 12, 24 and 48h period. Total protein levels and the phosphorylation status of STAT3 were determined by westernblot. Beta-tubulin and ERGIC53 respectively served as loading controls. The data-set shown represents 1 of 3 independent experiments.

Mentions: In keeping with previous reports documenting constitutive STAT3 expression and phosphorylation in human medulloblastoma biopsies, all 4 investigated medulloblastoma cell lines exhibited STAT3 phosphorylation at TYR705. Here we document for the first time that Pazopanib similar to Sorafenib reduced STAT3 phosphorylation in 3 of 4 medulloblastoma cell lines in a dose- (data not shown) and time-dependent manner (Figure 5). At clinically relevant concentrations Pazopanib and Sorafenib profoundly inhibit STAT3 phosphorylation in MEB-Med-8A, D283 Med and Daoy, but not in the most resistant cell line D341 Med [21-22].


In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy.

Craveiro RB, Ehrhardt M, Holst MI, Pietsch T, Dilloo D - Oncotarget (2014)

The anti-proliferative and pro-apoptotic effects of Pazopanib and Sorafenib are associated with a reduction of STAT3 phosphorylation at tyrosine 705In Daoy, MEB-Med-8A, D283 Med and D341 Med cells were treated with Pazopanib and Sorafenib at concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM) for a 1, 12, 24 and 48h period. Total protein levels and the phosphorylation status of STAT3 were determined by westernblot. Beta-tubulin and ERGIC53 respectively served as loading controls. The data-set shown represents 1 of 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196191&req=5

Figure 5: The anti-proliferative and pro-apoptotic effects of Pazopanib and Sorafenib are associated with a reduction of STAT3 phosphorylation at tyrosine 705In Daoy, MEB-Med-8A, D283 Med and D341 Med cells were treated with Pazopanib and Sorafenib at concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM) for a 1, 12, 24 and 48h period. Total protein levels and the phosphorylation status of STAT3 were determined by westernblot. Beta-tubulin and ERGIC53 respectively served as loading controls. The data-set shown represents 1 of 3 independent experiments.
Mentions: In keeping with previous reports documenting constitutive STAT3 expression and phosphorylation in human medulloblastoma biopsies, all 4 investigated medulloblastoma cell lines exhibited STAT3 phosphorylation at TYR705. Here we document for the first time that Pazopanib similar to Sorafenib reduced STAT3 phosphorylation in 3 of 4 medulloblastoma cell lines in a dose- (data not shown) and time-dependent manner (Figure 5). At clinically relevant concentrations Pazopanib and Sorafenib profoundly inhibit STAT3 phosphorylation in MEB-Med-8A, D283 Med and Daoy, but not in the most resistant cell line D341 Med [21-22].

Bottom Line: Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival.Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib.Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany. These authors contributed equally to this work.

ABSTRACT
Regardless of the recent advances in cytotoxic therapies, 30% of children diagnosed with medulloblastoma. succumb to the disease. Therefore, novel therapeutic approaches are warranted. Here we demonstrate that Pazopanib a clinically approved multi-kinase angiogenesis inhibitor (MKI) inhibits proliferation and apoptosis in medulloblastoma cell lines. Moreover, Pazopanib profoundly attenuates medulloblastoma cell migration, a prerequisite for tumor invasion and metastasis. In keeping with the observed anti-neoplastic activity of Pazopanib, we also delineate reduced phosphorylation of the STAT3 protein, a key regulator of medulloblastoma proliferation and cell survival. Finally, we document profound in vivo activity of Pazopanib in an orthotopic mouse model of the most aggressive c-myc amplified human medulloblastoma variant. Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival. Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib. Both compounds share a similar target profile but display different pharmacodynamics and pharmacokinetics with distinct cytotoxic activity in different tumor entities. Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.

Show MeSH
Related in: MedlinePlus