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

• 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
• DOI: 10.1371/journal.pone.0154612
• EISSN: 1932-6203

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.