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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 induce S-phase cell cycle arrestDaoy and MEB-Med8A cells were treated for 48h with concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). Subsequently cell cycle distribution was determined by Hoechst 33342 staining. The vehicle DMSO served as control. The lower panel depicts the reduction in cell density and changes in morphology for Daoy and MEB-Med-8a after drug exposure for 48h (scale bar 100 μm). Statistically significant differences from control are marked by an asterix (*p<0,05). The data shown represent five independent experiments.
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Figure 3: Pazopanib and Sorafenib induce S-phase cell cycle arrestDaoy and MEB-Med8A cells were treated for 48h with concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). Subsequently cell cycle distribution was determined by Hoechst 33342 staining. The vehicle DMSO served as control. The lower panel depicts the reduction in cell density and changes in morphology for Daoy and MEB-Med-8a after drug exposure for 48h (scale bar 100 μm). Statistically significant differences from control are marked by an asterix (*p<0,05). The data shown represent five independent experiments.

Mentions: MEB-Med-8A is of higher and Daoy of lower sensitivity to Pazopanib-mediated anti-proliferative effects, therefore these cell lines were chosen for cell cycle analysis after 48h exposure to the respective MKI. The vehicle DMSO served as control (Figure 3). MKI were applied at concentrations corresponding to patient plasma levels [21-22]. Treatment with either Pazopanib or Sorafenib induced a significant S-Phase arrest in MEB-Med-8A (Pazopanib 26.4±1.6%; Sorafenib 28.2±1.2%; DMSO 17.7±1.3%) and Daoy (Pazopanib 20.3±2.9%; Sorafenib 49.4±2.2%; DMSO 15.3±0.9%). Moreover, for Daoy an additional G2M-Phase arrest was detected in the presence of Sorafenib (Sorafenib 27.8±1.5% and DMSO 17.0±2.2%).


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 induce S-phase cell cycle arrestDaoy and MEB-Med8A cells were treated for 48h with concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). Subsequently cell cycle distribution was determined by Hoechst 33342 staining. The vehicle DMSO served as control. The lower panel depicts the reduction in cell density and changes in morphology for Daoy and MEB-Med-8a after drug exposure for 48h (scale bar 100 μm). Statistically significant differences from control are marked by an asterix (*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 3: Pazopanib and Sorafenib induce S-phase cell cycle arrestDaoy and MEB-Med8A cells were treated for 48h with concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). Subsequently cell cycle distribution was determined by Hoechst 33342 staining. The vehicle DMSO served as control. The lower panel depicts the reduction in cell density and changes in morphology for Daoy and MEB-Med-8a after drug exposure for 48h (scale bar 100 μm). Statistically significant differences from control are marked by an asterix (*p<0,05). The data shown represent five independent experiments.
Mentions: MEB-Med-8A is of higher and Daoy of lower sensitivity to Pazopanib-mediated anti-proliferative effects, therefore these cell lines were chosen for cell cycle analysis after 48h exposure to the respective MKI. The vehicle DMSO served as control (Figure 3). MKI were applied at concentrations corresponding to patient plasma levels [21-22]. Treatment with either Pazopanib or Sorafenib induced a significant S-Phase arrest in MEB-Med-8A (Pazopanib 26.4±1.6%; Sorafenib 28.2±1.2%; DMSO 17.7±1.3%) and Daoy (Pazopanib 20.3±2.9%; Sorafenib 49.4±2.2%; DMSO 15.3±0.9%). Moreover, for Daoy an additional G2M-Phase arrest was detected in the presence of Sorafenib (Sorafenib 27.8±1.5% and DMSO 17.0±2.2%).

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