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Article: Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma

TitleMechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma
Authors
KeywordsAurora kinase
Cell-cycle
Medulloblastoma
Molecular therapy
Tumor biology
Issue Date2015
Citation
Oncotarget, 2015, v. 6, n. 5, p. 3359-3374 How to Cite?
AbstractMedulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYCoverexpressing medulloblastoma cells with AZD1152-HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152- HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma.
Persistent Identifierhttp://hdl.handle.net/10722/313968
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorDiaz, Roberto Jose-
dc.contributor.authorGolbourn, Brian-
dc.contributor.authorFaria, Claudia-
dc.contributor.authorPicard, Daniel-
dc.contributor.authorShih, David-
dc.contributor.authorRaynaud, Denis-
dc.contributor.authorLeadly, Michael-
dc.contributor.authorMacKenzie, Danielle-
dc.contributor.authorBryant, Melissa-
dc.contributor.authorBebenek, Matthew-
dc.contributor.authorSmith, Christian A.-
dc.contributor.authorTaylor, Michael D.-
dc.contributor.authorHuang, Annie-
dc.contributor.authorRutka, James T.-
dc.date.accessioned2022-07-06T11:28:39Z-
dc.date.available2022-07-06T11:28:39Z-
dc.date.issued2015-
dc.identifier.citationOncotarget, 2015, v. 6, n. 5, p. 3359-3374-
dc.identifier.urihttp://hdl.handle.net/10722/313968-
dc.description.abstractMedulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYCoverexpressing medulloblastoma cells with AZD1152-HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152- HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma.-
dc.languageeng-
dc.relation.ispartofOncotarget-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAurora kinase-
dc.subjectCell-cycle-
dc.subjectMedulloblastoma-
dc.subjectMolecular therapy-
dc.subjectTumor biology-
dc.titleMechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.18632/oncotarget.3245-
dc.identifier.pmid25739120-
dc.identifier.pmcidPMC4413659-
dc.identifier.scopuseid_2-s2.0-84923315705-
dc.identifier.volume6-
dc.identifier.issue5-
dc.identifier.spage3359-
dc.identifier.epage3374-
dc.identifier.eissn1949-2553-
dc.identifier.isiWOS:000352694400061-

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