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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| المؤلفون: | Pirjo Laakkonen, Joni Merisaari, Milena Doroszko, David Kastrinsky, Oxana V. Denisova, William P.J. Leenders, Goutham Narla, Michael Ohlmeyer, Nilesh Zaware, Vadim Le Joncour, Patrik Johansson, Jukka Westermarck, Sven Nelander |
| المساهمون: | CAN-PRO - Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki Institute of Life Science HiLIFE, Infra, Pirjo Maarit Laakkonen / Principal Investigator, KEK Meilahti, Research Programs Unit |
| المصدر: | Brain Communications, 2 Brain Communications Brain Communications, 2, 1 |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, EGFR, Cell- och molekylärbiologi, Phosphatase, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), Blood–brain barrier, 3124 Neurology and psychiatry, SUBTYPES, CIP2A, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, In vivo, Glioma, medicine, PME-1, Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci), GENE-EXPRESSION, E98, Cancer och onkologi, DT-061, IDENTIFICATION, Chemistry, Kinase, 3112 Neurosciences, General Engineering, tricyclic neurological drugs, Protein phosphatase 2, medicine.disease, CANCER, Small molecule, 3. Good health, TARGET, 030104 developmental biology, medicine.anatomical_structure, Cell culture, 030220 oncology & carcinogenesis, Cancer and Oncology, Cancer research, GLIOMA MODELS, Original Article, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Cell and Molecular Biology |
| الوصف: | 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 specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies. This study introduces the therapeutic potential of orally bioavailable protein phosphatase 2A reactivating small molecules, in an intracranial infiltrative glioblastoma model. In vitro, small molecule activators of protein phosphatase 2A are effective against 14 different glioblastoma cell lines, regardless of their subtype, genetic background or stemness properties. Conceptually, the results reveal drug-elicited tumour suppressor reactivation for glioblastoma. Graphical Abstract Graphical Abstract |
| وصف الملف: | application/pdf |
| تدمد: | 2632-1297 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3dfc8c7f361e34aa042d8909e86ce396 https://hdl.handle.net/2066/226259 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3dfc8c7f361e34aa042d8909e86ce396 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26321297 |
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