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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

Pazopanib and Sorafenib exhibit anti-proliferative and pro-apoptotic effects in medulloblastoma cell linesIn a combined proliferation-apoptosis assay based on a CFSE-7AAD-Annexin-V staining the capacity of Pazopanib and Sorafenib to inhibit proliferation (a) and induce apoptosis (b) in medulloblastoma cell lines was determined. The cells were treated for 24, 48 and 72h with MKI concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). The vehicle DMSO served as control. The proliferation were normalized with the DMSO control. Statistically significant differences compared to control are marked by an asterisk (*p<0,05). The data represent four independent experiments.
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Figure 2: Pazopanib and Sorafenib exhibit anti-proliferative and pro-apoptotic effects in medulloblastoma cell linesIn a combined proliferation-apoptosis assay based on a CFSE-7AAD-Annexin-V staining the capacity of Pazopanib and Sorafenib to inhibit proliferation (a) and induce apoptosis (b) in medulloblastoma cell lines was determined. The cells were treated for 24, 48 and 72h with MKI concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). The vehicle DMSO served as control. The proliferation were normalized with the DMSO control. Statistically significant differences compared to control are marked by an asterisk (*p<0,05). The data represent four independent experiments.

Mentions: After 72h treatment significant suppression of cellular growth was observed in 3 of 4 investigated medulloblastoma cell lines (Figure 2a). Pazopanib and Sorafenib inhibited proliferation in MEB-Med-8A (Pazopanib: 52.8±3.6%, Sorafenib: 74.8±6%) and D283 Med (Pazopanib: 30.8±5.9%; Sorafenib: 33.9±9.2%) to a similar extent. In Daoy the suppression effect of Sorafenib was more pronounced (Pazopanib: 12.7±4.8%; Sorafenib: 76±2.2%), while D341 proved resistant to both compounds.


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 exhibit anti-proliferative and pro-apoptotic effects in medulloblastoma cell linesIn a combined proliferation-apoptosis assay based on a CFSE-7AAD-Annexin-V staining the capacity of Pazopanib and Sorafenib to inhibit proliferation (a) and induce apoptosis (b) in medulloblastoma cell lines was determined. The cells were treated for 24, 48 and 72h with MKI concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). The vehicle DMSO served as control. The proliferation were normalized with the DMSO control. Statistically significant differences compared to control are marked by an asterisk (*p<0,05). The data represent four independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Pazopanib and Sorafenib exhibit anti-proliferative and pro-apoptotic effects in medulloblastoma cell linesIn a combined proliferation-apoptosis assay based on a CFSE-7AAD-Annexin-V staining the capacity of Pazopanib and Sorafenib to inhibit proliferation (a) and induce apoptosis (b) in medulloblastoma cell lines was determined. The cells were treated for 24, 48 and 72h with MKI concentrations corresponding to patient's plasma levels (Pazopanib 15 μM and Sorafenib 10 μM). The vehicle DMSO served as control. The proliferation were normalized with the DMSO control. Statistically significant differences compared to control are marked by an asterisk (*p<0,05). The data represent four independent experiments.
Mentions: After 72h treatment significant suppression of cellular growth was observed in 3 of 4 investigated medulloblastoma cell lines (Figure 2a). Pazopanib and Sorafenib inhibited proliferation in MEB-Med-8A (Pazopanib: 52.8±3.6%, Sorafenib: 74.8±6%) and D283 Med (Pazopanib: 30.8±5.9%; Sorafenib: 33.9±9.2%) to a similar extent. In Daoy the suppression effect of Sorafenib was more pronounced (Pazopanib: 12.7±4.8%; Sorafenib: 76±2.2%), while D341 proved resistant to both compounds.

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