A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties
Preventing neuronal death is a priority for treating neurological diseases. However, therapies that inhibit pathological neuron loss could promote tumorigenesis by preventing the physiological death of cancerous cells. To avert this, we targeted the transcriptional upregulation of p21waf1/cip1 (p21)...
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Elsevier
2013-01-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112003038 |
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doaj-7971307ece754a39ac7b44c1513b518f |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thong C. Ma Brett Langley Brian Ko Na Wei Irina G. Gazaryan Neela Zareen Darrell J. Yamashiro Dianna E. Willis Rajiv R. Ratan |
spellingShingle |
Thong C. Ma Brett Langley Brian Ko Na Wei Irina G. Gazaryan Neela Zareen Darrell J. Yamashiro Dianna E. Willis Rajiv R. Ratan A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties Neurobiology of Disease p21 Neuroprotection Antitumor Prolyl hydroxylase inhibitors Neuronal oxidative stress |
author_facet |
Thong C. Ma Brett Langley Brian Ko Na Wei Irina G. Gazaryan Neela Zareen Darrell J. Yamashiro Dianna E. Willis Rajiv R. Ratan |
author_sort |
Thong C. Ma |
title |
A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties |
title_short |
A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties |
title_full |
A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties |
title_fullStr |
A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties |
title_full_unstemmed |
A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties |
title_sort |
screen for inducers of p21waf1/cip1 identifies hif prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2013-01-01 |
description |
Preventing neuronal death is a priority for treating neurological diseases. However, therapies that inhibit pathological neuron loss could promote tumorigenesis by preventing the physiological death of cancerous cells. To avert this, we targeted the transcriptional upregulation of p21waf1/cip1 (p21), an endogenous tumor suppressor with neuroprotective and pro-regenerative activity. We identified potential p21 indcuers by screening a FDA-approved drug and natural product small molecule library against hippocampal HT22 cells stably expressing a luciferase reporter driven by the proximal 60 bp of the p21 promoter, and tested them for neuroprotection from glutathione depletion mediated oxidative stress, and cytotoxicity to cancer cell lines (DLD-1, Neuro-2A, SH-SY5Y, NGP, CHLA15, CHP212, and SK-N-SH) in vitro. Of the p21 inducers identified, only ciclopirox, a hypoxia-inducible factor prolyl-4-hydroxylase (HIF–PHD) inhibitor, simultaneously protected neurons from glutathione depletion and decreased cancer cell proliferation at concentrations that were not basally toxic to neurons. We found that other structurally distinct HIF–PHD inhibitors (desferrioxamine, 3,4-dihydroxybenzoate, and dimethyloxalyl glycine) also protected neurons at concentrations that killed cancer cells. HIF–PHD inhibitors stabilize HIF transcription factors, mediating genetic adaptation to hypoxia. While augmenting HIF stability is believed to promote tumorigenesis, we found that chronic HIF–PHD inhibition killed cancer cells, suggesting a protumorigenic role for these enzymes. Moreover, our findings suggest that PHD inhibitors can be used to treat neurological disease without significant concern for cell-autonomous tumor promotion. |
topic |
p21 Neuroprotection Antitumor Prolyl hydroxylase inhibitors Neuronal oxidative stress |
url |
http://www.sciencedirect.com/science/article/pii/S0969996112003038 |
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doaj-7971307ece754a39ac7b44c1513b518f2021-03-22T12:39:07ZengElsevierNeurobiology of Disease1095-953X2013-01-01491321A screen for inducers of p21waf1/cip1 identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor propertiesThong C. Ma0Brett Langley1Brian Ko2Na Wei3Irina G. Gazaryan4Neela Zareen5Darrell J. Yamashiro6Dianna E. Willis7Rajiv R. Ratan8Burke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10065, USA; Corresponding authors at: Burke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA. Fax: +1 914 597 2225.Burke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10065, USABurke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10065, USADepartment of Pediatrics, Pathology, and Cell Biology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, New York, NY 10032, USABurke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10065, USADepartment of Pathology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY, 10032, USADepartment of Pediatrics, Pathology, and Cell Biology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, New York, NY 10032, USABurke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10065, USABurke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10065, USA; Corresponding authors at: Burke-Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA. Fax: +1 914 597 2225.Preventing neuronal death is a priority for treating neurological diseases. However, therapies that inhibit pathological neuron loss could promote tumorigenesis by preventing the physiological death of cancerous cells. To avert this, we targeted the transcriptional upregulation of p21waf1/cip1 (p21), an endogenous tumor suppressor with neuroprotective and pro-regenerative activity. We identified potential p21 indcuers by screening a FDA-approved drug and natural product small molecule library against hippocampal HT22 cells stably expressing a luciferase reporter driven by the proximal 60 bp of the p21 promoter, and tested them for neuroprotection from glutathione depletion mediated oxidative stress, and cytotoxicity to cancer cell lines (DLD-1, Neuro-2A, SH-SY5Y, NGP, CHLA15, CHP212, and SK-N-SH) in vitro. Of the p21 inducers identified, only ciclopirox, a hypoxia-inducible factor prolyl-4-hydroxylase (HIF–PHD) inhibitor, simultaneously protected neurons from glutathione depletion and decreased cancer cell proliferation at concentrations that were not basally toxic to neurons. We found that other structurally distinct HIF–PHD inhibitors (desferrioxamine, 3,4-dihydroxybenzoate, and dimethyloxalyl glycine) also protected neurons at concentrations that killed cancer cells. HIF–PHD inhibitors stabilize HIF transcription factors, mediating genetic adaptation to hypoxia. While augmenting HIF stability is believed to promote tumorigenesis, we found that chronic HIF–PHD inhibition killed cancer cells, suggesting a protumorigenic role for these enzymes. Moreover, our findings suggest that PHD inhibitors can be used to treat neurological disease without significant concern for cell-autonomous tumor promotion.http://www.sciencedirect.com/science/article/pii/S0969996112003038p21NeuroprotectionAntitumorProlyl hydroxylase inhibitorsNeuronal oxidative stress |