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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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Pazopanib and Sorafenib impair colony formation of medulloblastoma cellsDaoy and MEB-Med-8A cells were exposed to 15 μM of Pazopanib and 10 μM of Sorafenib respectively for 48h. Subsequently the cells were maintained in standard growth medium for 7 days and colony formation and colony size were assessed. Statistically significant differences are marked by an asterisk (*p<0.05). The data shown represent five independent experiments.
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Figure 4: Pazopanib and Sorafenib impair colony formation of medulloblastoma cellsDaoy and MEB-Med-8A cells were exposed to 15 μM of Pazopanib and 10 μM of Sorafenib respectively for 48h. Subsequently the cells were maintained in standard growth medium for 7 days and colony formation and colony size were assessed. Statistically significant differences are marked by an asterisk (*p<0.05). The data shown represent five independent experiments.

Mentions: We also analyzed the capability of Pazopanib and Sorafenib to interfere with clonogenicity of the adherent cell lines MEB-Med-8A and Daoy (Figure 4). For this purpose MEB-Med-8A and Daoy and were exposed to clinically relevant concentrations of Pazopanib and Sorafenib respectively for 48h. Thereafter the cells were cultured for 7 days in standard medium without drugs. The number of colonies (NC) and the average colonies size (ACS) were determined.


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)

Pazopanib and Sorafenib impair colony formation of medulloblastoma cellsDaoy and MEB-Med-8A cells were exposed to 15 μM of Pazopanib and 10 μM of Sorafenib respectively for 48h. Subsequently the cells were maintained in standard growth medium for 7 days and colony formation and colony size were assessed. Statistically significant differences are marked by an asterisk (*p<0.05). The data shown represent five independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Pazopanib and Sorafenib impair colony formation of medulloblastoma cellsDaoy and MEB-Med-8A cells were exposed to 15 μM of Pazopanib and 10 μM of Sorafenib respectively for 48h. Subsequently the cells were maintained in standard growth medium for 7 days and colony formation and colony size were assessed. Statistically significant differences are marked by an asterisk (*p<0.05). The data shown represent five independent experiments.
Mentions: We also analyzed the capability of Pazopanib and Sorafenib to interfere with clonogenicity of the adherent cell lines MEB-Med-8A and Daoy (Figure 4). For this purpose MEB-Med-8A and Daoy and were exposed to clinically relevant concentrations of Pazopanib and Sorafenib respectively for 48h. Thereafter the cells were cultured for 7 days in standard medium without drugs. The number of colonies (NC) and the average colonies size (ACS) were determined.

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