PI3Kβ inhibitor AZD6482 exerts antiproliferative activity and induces apoptosis in human glioblastoma cells

Glioblastoma is the most common type of primary brain tumour in adults, and its pathogenesis is particularly complicated. Among the many possible mechanisms underlying its pathogenesis, hyperactivation of the PI3K/Akt pathway is essential to the occurrence and development of glioma through the loss of PTEN or somatic activating mutations in PIK3CA. In the present study, we investigated the effect of the PI3Kβ inhibitor AZD6482 on glioma cells. The CCK-8 assay showed dose-dependent cytotoxicity in glioma cell lines treated with AZD6482. Additionally, AZD6482 treatment was found to significantly induce apoptosis and cell cycle arrest as detected using flow cytometry. Moreover, as shown using western blot analysis, the levels of p-AKT, p-GSK-3β, Bcl-2, and cyclin D1 were decreased after AZD6482 treatment. In addition, we found that AZD6482 inhibited the migration and invasion of glioma cells as detected by wound healing and Transwell invasion assays. Taken together, our findings indicate that AZD6482 exerts an antitumour effect by inhibiting proliferation and inducing apoptosis in human glioma cells. AZD6482 may be applied as an adjuvant therapy to improve the therapeutic efficacy of glioblastoma treatment.

[1]  L. Deangelis,et al.  Glioblastoma and other malignant gliomas: a clinical review. , 2013, JAMA.

[2]  D. Trafalis,et al.  Glioblastoma multiforme: Pathogenesis and treatment. , 2015, Pharmacology & therapeutics.

[3]  Stephen T. C. Wong,et al.  Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma , 2018, Molecular oncology.

[4]  [World Health Organization classification of tumours of the central nervous system: a summary]. , 2016, Zhonghua bing li xue za zhi = Chinese journal of pathology.

[5]  T. Roberts,et al.  A PI3K p110β–Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis , 2015, Nature Communications.

[6]  J. Paramio,et al.  Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway. , 2018, Oral oncology.

[7]  Sridhar Ramaswamy,et al.  Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells , 2012, Nucleic Acids Res..

[8]  F. Liu,et al.  GSK3β-dependent cyclin D1 and cyclin E1 degradation is indispensable for NVP-BEZ235 induced G0/G1 arrest in neuroblastoma cells , 2017, Cell cycle.

[9]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[10]  Jing Zhang,et al.  Corrigendum: Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis , 2016, Nature.

[11]  M. Barbacid,et al.  Cell cycle, CDKs and cancer: a changing paradigm , 2009, Nature Reviews Cancer.

[12]  B. Vanhaesebroeck,et al.  The emerging mechanisms of isoform-specific PI3K signalling , 2010, Nature Reviews Molecular Cell Biology.

[13]  Gelareh Zadeh,et al.  Glioblastoma: pathology, molecular mechanisms and markers , 2015, Acta Neuropathologica.

[14]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[15]  Lewis C. Cantley,et al.  The PI3K Pathway in Human Disease , 2017, Cell.

[16]  The Cancer Genome Atlas Research Network.  Corrigendum: Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2013, Nature.

[17]  E. Harrington,et al.  Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer , 2018, Oncotarget.

[18]  S. Reuveny,et al.  Unraveling the Inconsistencies of Cardiac Differentiation Efficiency Induced by the GSK3β Inhibitor CHIR99021 in Human Pluripotent Stem Cells , 2018, Stem cell reports.

[19]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[20]  Hilla Peretz,et al.  Ju n 20 03 Schrödinger ’ s Cat : The rules of engagement , 2003 .

[21]  Roland Eils,et al.  Complex heatmaps reveal patterns and correlations in multidimensional genomic data , 2016, Bioinform..

[22]  Yan Wei,et al.  Curcumol induces cell cycle arrest in colon cancer cells via reactive oxygen species and Akt/ GSK3β/cyclin D1 pathway. , 2018, Journal of ethnopharmacology.

[23]  Yongqiang Zhu,et al.  PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts , 2011, Journal of Neuro-Oncology.

[24]  A. Bode,et al.  Dactylone inhibits epidermal growth factor-induced transformation and phenotype expression of human cancer cells and induces G1-S arrest and apoptosis. , 2007, Cancer research.

[25]  Simon T Barry,et al.  Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. , 2015, Cancer cell.

[26]  M. Bally,et al.  Combined RNAi-Mediated Suppression of Rictor and EGFR Resulted in Complete Tumor Regression in an Orthotopic Glioblastoma Tumor Model , 2013, PloS one.

[27]  Seema Patel,et al.  Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[28]  A. Toker,et al.  PI3K signaling in cancer: beyond AKT. , 2017, Current opinion in cell biology.

[29]  M. Sanson,et al.  Progestin-associated shift of meningioma mutational landscape , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[30]  Alice T. Loo,et al.  PTEN-deficient cancers depend on PIK3CB , 2008, Proceedings of the National Academy of Sciences.

[31]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[32]  N. Gray,et al.  Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. , 2012, Cancer discovery.