Treatment with the PI3K inhibitor buparlisib (NVP-BKM120) suppresses the growth of established patient-derived GBM xenografts and prolongs survival in nude rats

Autor: Inger Anne Netland, Linda Sleire, B. S. Skeie, Dorota Goplen, Hrvoje Miletic, Lina Leiss, Hilde Elise Førde, Mohummad Aminur Rahman, Per Øyvind Enger
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Pathology
Cancer Research
medicine.medical_treatment
Cell
Proliferation
Buparlisib
Aminopyridines
Apoptosis
PI3K
Targeted therapy
chemistry.chemical_compound
0302 clinical medicine
Medicine
Phosphorylation
Phosphoinositide-3 Kinase Inhibitors
Brain Neoplasms
medicine.anatomical_structure
Oncology
Neurology
030220 oncology & carcinogenesis
medicine.medical_specialty
Cell Survival
Morpholines
Clinical Neurology
Antineoplastic Agents
03 medical and health sciences
Rats
Nude
In vivo
Patient-derived xenograft
Glioma
Cell Line
Tumor
Animals
Humans
PI3K/AKT/mTOR pathway
Cell Proliferation
Chemotherapy
business.industry
Cell growth
Brain tumours
medicine.disease
Survival Analysis
Xenograft Model Antitumor Assays
030104 developmental biology
chemistry
Cancer research
Laboratory Investigation
Neurology (clinical)
business
Glioblastoma
Proto-Oncogene Proteins c-akt
Zdroj: Journal of Neuro-Oncology
ISSN: 1573-7373
0167-594X
Popis: Glioblastomas (GBMs) are aggressive brain tumours with a dismal prognosis, despite combined surgery, radio- and chemotherapy. Close to 90 % of all GBMs harbour a deregulated PI3K pathway, which is essential in regulating central cellular functions such as proliferation, cell growth, motility and survival. Thus, PI3K represents a potential target for molecular therapy in GBM. We investigated the anti-tumour efficacy of the PI3K inhibitor buparlisib (NVP-BKM120) in GBM cell lines in vitro and in vivo, when treatment was initiated after MRI-confirmed tumour engraftment. We found that buparlisib inhibited glioma cell proliferation in a dose dependent manner, demonstrated by MTS assay, manual cell count and BrdU incorporation. A dose dependent increase in apoptosis was observed through flow cytometric analysis. Furthermore, by immunocytochemistry and western blot, we found a dose dependent inhibition of Akt phosphorylation. Moreover, buparlisib prolonged survival of nude rats harboring human GBM xenografts in three independent studies and reduced the tumours’ volumetric increase, as determined by MRI. In addition, histological analyses of xenograft rat brains showed necrotic areas and change in tumour cell nuclei in buparlisib-treated animals. The rats receiving buparlisib maintained their weight, activity level and food- and water intake. In conclusion, buparlisib effectively inhibits glioma cell proliferation in vitro and growth of human GBM xenografts in nude rats. Moreover, the compound is well tolerated when administered at doses providing anti-tumour efficacy. Thus, buparlisib may have a future role in glioma therapy, and further studies are warranted to validate this compound for human use. Electronic supplementary material The online version of this article (doi:10.1007/s11060-016-2158-1) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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