مورد إلكتروني
Monotherapy efficacy of blood-brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma
| العنوان: | Monotherapy efficacy of blood-brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma |
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| بيانات النشر: | Uppsala universitet, Neuroonkologi Univ Turku, Turku Biosci Ctr, Tykistokatu 6A, Turku 20520, Finland.;Abo Akad Univ, Tykistokatu 6A, Turku 20520, Finland.;Univ Turku, Inst Biomed, Turku 20520, Finland. Univ Turku, Turku Biosci Ctr, Tykistokatu 6A, Turku 20520, Finland.;Abo Akad Univ, Tykistokatu 6A, Turku 20520, Finland. Univ Helsinki, Fac Med, Translat Canc Med Res Program, Helsinki 00014, Finland. Radboud Inst Mol Life Sci, Dept Biochem, NL-6525 Nijmegen, Netherlands. Icahn Sch Med Mt Sinai, New York, NY 10029 USA.;Donald & Barbara Zucker Sch Med Hofstra Northwell, Hempstead, NY 11549 USA. Icahn Sch Med Mt Sinai, New York, NY 10029 USA. Univ Michigan, Dept Internal Med, Div Genet Med, Ann Arbor, MI 48109 USA. Univ Helsinki, Fac Med, Translat Canc Med Res Program, Helsinki 00014, Finland.;Univ Helsinki, Lab Anim Ctr, Helsinki Inst Life Sci HiLIFE, Helsinki 00014, Finland. Icahn Sch Med Mt Sinai, New York, NY 10029 USA.;Atux Iskay LLC, Plainsboro, NJ 08536 USA. Univ Turku, Turku Biosci Ctr, Tykistokatu 6A, Turku 20520, Finland.;Abo Akad Univ, Tykistokatu 6A, Turku 20520, Finland.;Univ Turku, Inst Biomed, Turku 20520, Finland. Oxford University Press (OUP) 2020 |
| تفاصيل مُضافة: | Merisaari, Joni Denisova, Oxana, V Doroszko, Milena Le Joncour, Vadim Johansson, Patrik Leenders, William P. J. Kastrinsky, David B. Zaware, Nilesh Narla, Goutham Laakkonen, Pirjo Nelander, Sven Ohlmeyer, Michael Westermarck, Jukka |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood-brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood-brain barrier-permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting spec |
| مصطلحات الفهرس: | PME-1, CIP2A, DT-061, E98, tricyclic neurological drugs, Cell and Molecular Biology, Cell- och molekylärbiologi, Cancer and Oncology, Cancer och onkologi, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci), Article in journal, info:eu-repo/semantics/article, text |
| DOI: | 10.1093.braincomms.fcaa002 |
| URL: | Brain Communications, 2020, 2:1 |
| الإتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | application/pdf English |
| أرقام أخرى: | UPE oai:DiVA.org:uu-423465 0000-0003-1758-1262 doi:10.1093/braincomms/fcaa002 PMID 32954276 ISI:000574931600002 1235298294 |
| المصدر المساهم: | UPPSALA UNIV LIBR From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1235298294 |
| قاعدة البيانات: | OAIster |
| DOI: | 10.1093.braincomms.fcaa002 |
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