Phosphatidylinositol 3-Kinase/AKT Pathway Inhibition by Doxazosin Promotes Glioblastoma Cells Death, Upregulation of p53 and Triggers Low Neurotoxicity

Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazo...

Full description

Saved in:

Bibliographic Details
Published in:	PloS one Vol. 11; no. 4; p. e0154612
Main Authors:	Gaelzer, Mariana Maier, Coelho, Bárbara Paranhos, de Quadros, Alice Hoffmann, Hoppe, Juliana Bender, Terra, Silvia Resende, Guerra, Maria Cristina Barea, Usach, Vanina, Guma, Fátima Costa Rodrigues, Gonçalves, Carlos Alberto Saraiva, Setton-Avruj, Patrícia, Battastini, Ana Maria Oliveira, Salbego, Christianne Gazzana
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 28-04-2016 Public Library of Science (PLoS)
Subjects:	1-Phosphatidylinositol 3-kinase AKT protein Animals Antihypertensives Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Astrocytes Astrocytes - drug effects Biology and Life Sciences Brain Brain cancer Brain Neoplasms - drug therapy Brain research Brain tumors Cancer therapies Caspase Caspase 3 - metabolism Caspase-3 Cell activation Cell culture Cell cycle Cell death Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Chemical compounds Chemotherapy Chromones - pharmacology Confocal microscopy Cytometry Dosage and administration Doxazosin Doxazosin - pharmacology Doxazosin - toxicity Drug development Drugs Enzyme Activation - drug effects Enzyme inhibitors Flow cytometry G1 phase G1 Phase Cell Cycle Checkpoints - drug effects Glioblastoma Glioblastoma - drug therapy Glioblastoma cells Glioblastomas Glioma Glycogen Synthase Kinase 3 beta - biosynthesis Hippocampus Hippocampus - drug effects Humans Inhibition Inhibitors Irradiation Kinases Laboratory animals Lapatinib Medical prognosis Medical research Medicine and Health Sciences Metastasis Microscopy Morpholines - pharmacology Mortality Neurotoxicity p53 Protein Pharmacology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Prostate cancer Protein-tyrosine kinase Proteins Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Quinazolines - pharmacology Rats Rats, Wistar Research and Analysis Methods Surgery Temozolomide Tumor cells Tumor Suppressor Protein p53 - biosynthesis Tumorigenesis Tumors Tyrosine Up-regulation Brazil Rio Grande do Sul Brazil Argentina Grand Island New York United States > US
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin's (an antihypertensive drug) activity against glioblastoma cells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin's effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3β and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent.
Bibliography:	Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: MMG PS-A CGS. Performed the experiments: MMG BPC AHQ MCBG. Analyzed the data: MMG BPC JBH SRT VU. Contributed reagents/materials/analysis tools: FCRG CASG PS-A AMOB CGS. Wrote the paper: MMG BPC JBH CGS.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0154612