title: A screen for inducers of p21(waf1/cip1) identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties.
abstract: 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 p21(waf1/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 60bp 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.
authors.affiliation: 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, USA. Electronic address: tma@burke.org.
authors.forename: Thong C
authors.initials: TC
authors.lastname: Ma
authors.affiliation: 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, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Langley
authors.affiliation: 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, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ko
authors.affiliation: Department of Pediatrics, Pathology, and Cell Biology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, New York, NY 10032, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: 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, USA.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Gazaryan
authors.affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Neela
authors.initials: N
authors.lastname: Zareen
authors.affiliation: Department of Pediatrics, Pathology, and Cell Biology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, New York, NY 10032, USA.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
authors.affiliation: 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, USA.
authors.forename: Dianna E
authors.initials: DE
authors.lastname: Willis
authors.affiliation: 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, USA. Electronic address: rratan@burke.org.
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018696:Neuroprotective Agents; D064800:Prolyl-Hydroxylase Inhibitors; D054852:Small Molecule Libraries