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

MAIER GAELZER M; PARANHOS COELHO BARBARA; HOFFMAN DE QUADROS ALICE; BENDER HOPPE JULIANA; RESENDE TERRA SILVIA; BAREA GUERRA MARÍA CRISTINA; USACH VANINA; COSTA RODRIGUEZ GUMA FÁTIMA; SARAIVA GONZALEZ CARLOS ALBERTO; SETTON, CP; OLIVEIRA BATTASTINI ANA MARÍA; GAZANNA SALGUEDO CHRISTIANNE

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2016

1932-6203

Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapywith temozolomide concomitant with surgical resection and/or irradiation. However,a number of cases are resistant to temozolomide, as well as the human glioblastoma cellline U138-MG. We investigated doxazosin?s (an antihypertensive drug) activity against glioblastomacells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypichippocampal cultures. For this study, the following methods were used: citotoxicityassays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosininduces cell death on C6 and U138-MG cells. We observed that doxazosin?s effects onthe PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastomacells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activitiesof proteins downstream of Akt we observed upregulation of GSK-3β and p53. This led tocell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrestat G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinaseinhibitor, as a comparison with doxazosin because they present similar chemical structure.We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic culturesand observed that doxazosin induced cell death on a small percentage of non-tumorcells. Aggressiveness of glioblastoma tumors and dismal prognosis require development ofnew 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 doxazosinas an attractive therapeutic antiglioma agent.