Dual Effect of Doxazosin: Anticancer Activity on SH-SY5Y Neuroblastoma Cells and Neuroprotection on an In Vitro Model of Alzheimer's Disease
| Autor: | Fernanda dos Santos Petry, Juliana Bender Hoppe, Fátima Theresinha Costa Rodrigues Guma, Mariana Maier Gaelzer, Bárbara Paranhos Coelho, Christianne Gazzana Salbego, Vera Maria Treis Trindade |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine SH-SY5Y Cellular differentiation Antineoplastic Agents urologic and male genital diseases Hippocampus Neuroprotection Neuroblastoma 03 medical and health sciences Organ Culture Techniques 0302 clinical medicine Alzheimer Disease Cell Line Tumor Glioma medicine Doxazosin Animals Humans Cytotoxic T cell Rats Wistar Dose-Response Relationship Drug business.industry General Neuroscience medicine.disease Rats ErbB Receptors Neuroprotective Agents 030104 developmental biology Apoptosis Adrenergic alpha-1 Receptor Antagonists Cancer research business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neuroscience. 404:314-325 |
| ISSN: | 0306-4522 |
| Popis: | Several studies have demonstrated the antitumor effect of doxazosin, an α1-adrenergic blocker, against glioma and breast, bladder and prostate cancers. Doxazosin is also being evaluated as a treatment for posttraumatic stress disorder (PTSD) and alcoholism, and α1-adrenergic blockers have been linked to neuroprotection in neurodegenerative disorders, such as Alzheimer's Disease (AD). Cancer and AD have an inverse relationship in many aspects, with several factors that contribute to apoptosis inhibition and proliferation being increased in cancers but decreased in AD. Neuroblastoma (NB) is a pediatric tumor derived from embryonic neural-crest cells, with an overall cure rate of 40%, despite aggressive treatment. Thus, due to the need of new therapeutic strategies against NB and neurodegenerative disorders and the inverse relationship between these diseases, we investigated whether doxazosin may serve as an antitumor and neuroprotective agent. We analyzed the drug's effects on undifferentiated and retinoic acid-differentiated SH-SY5Y human NB cells and on an in vitro model of organotypic hippocampal cultures exposed to amyloid-β. Doxazosin showed antitumor effect on undifferentiated NB cells by induction of apoptosis, necrosis, cell cycle arrest and decrease of p-EGFRTyr1048 levels. On differentiated cells, doxazosin was less cytotoxic and increased p-EGFRTyr1048, p-AktSer473 and p-GSK-3βSer9 levels. Moreover, the drug was able to protect hippocampal slices from amyloid-β toxicity through prevention of GSK-3β activation and of Tau hyperphosphorylation. Therefore, our results show that doxazosin has antitumor activity against undifferentiated NB and is neuroprotective on an in vitro model of Alzheimer's disease. |
| Databáze: | OpenAIRE |
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