The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway
Abstract A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor‐initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1‐...
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Springer Nature
2016-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505421 |
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| author | Suzana Assad Kahn Silvia Lima Costa Sharareh Gholamin Ryan T Nitta Luiz Gustavo Dubois Marie Fève Maria Zeniou Paulo Lucas Cerqueira Coelho Elias El‐Habr Josette Cadusseau Pascale Varlet Siddhartha S Mitra Bertrand Devaux Marie‐Claude Kilhoffer Samuel H Cheshier Vivaldo Moura‐Neto Jacques Haiech Marie‐Pierre Junier Hervé Chneiweiss |
| author_facet | Suzana Assad Kahn Silvia Lima Costa Sharareh Gholamin Ryan T Nitta Luiz Gustavo Dubois Marie Fève Maria Zeniou Paulo Lucas Cerqueira Coelho Elias El‐Habr Josette Cadusseau Pascale Varlet Siddhartha S Mitra Bertrand Devaux Marie‐Claude Kilhoffer Samuel H Cheshier Vivaldo Moura‐Neto Jacques Haiech Marie‐Pierre Junier Hervé Chneiweiss |
| author_sort | Suzana Assad Kahn |
| collection | DOAJ |
| description | Abstract A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor‐initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1‐ and α2B‐adrenergic receptor antagonist, as the most potent inducer of patient‐derived glioblastoma‐initiating cell death. Prazosin triggered apoptosis of glioblastoma‐initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient‐derived glioblastoma‐initiating cells, and increased survival of glioblastoma‐bearing mice. We found that prazosin acted in glioblastoma‐initiating cells independently from adrenergic receptors. Its off‐target activity occurred via a PKCδ‐dependent inhibition of the AKT pathway, which resulted in caspase‐3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin‐treated glioblastoma‐initiating cells, as well as prazosin‐induced apoptosis. Based on these data, we conclude that prazosin, an FDA‐approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ‐dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients. |
| format | Article |
| id | doaj-art-e0c2de418b164543ac5b7d7885f022cd |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e0c2de418b164543ac5b7d7885f022cd2025-08-20T04:02:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-04-018551152610.15252/emmm.201505421The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathwaySuzana Assad Kahn0Silvia Lima Costa1Sharareh Gholamin2Ryan T Nitta3Luiz Gustavo Dubois4Marie Fève5Maria Zeniou6Paulo Lucas Cerqueira Coelho7Elias El‐Habr8Josette Cadusseau9Pascale Varlet10Siddhartha S Mitra11Bertrand Devaux12Marie‐Claude Kilhoffer13Samuel H Cheshier14Vivaldo Moura‐Neto15Jacques Haiech16Marie‐Pierre Junier17Hervé Chneiweiss18INSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSINSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSDepartment of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford UniversityDepartment of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford UniversityINSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSLaboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200Laboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200INSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSINSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSUMR INSERM 955‐Team 10, Faculté des Sciences et Technologies UPECDepartment of Neuropathology, Sainte‐Anne HospitalDepartment of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford UniversityINSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSLaboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford UniversityInstituto Estadual do Cérebro Paulo NiemeyerLaboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200INSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSINSERM, UMR‐S 1130, Neuroscience Paris Seine‐IBPSAbstract A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor‐initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1‐ and α2B‐adrenergic receptor antagonist, as the most potent inducer of patient‐derived glioblastoma‐initiating cell death. Prazosin triggered apoptosis of glioblastoma‐initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient‐derived glioblastoma‐initiating cells, and increased survival of glioblastoma‐bearing mice. We found that prazosin acted in glioblastoma‐initiating cells independently from adrenergic receptors. Its off‐target activity occurred via a PKCδ‐dependent inhibition of the AKT pathway, which resulted in caspase‐3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin‐treated glioblastoma‐initiating cells, as well as prazosin‐induced apoptosis. Based on these data, we conclude that prazosin, an FDA‐approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ‐dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.https://doi.org/10.15252/emmm.201505421gliomaGL261rottlerinsh PKCδδV1.1 |
| spellingShingle | Suzana Assad Kahn Silvia Lima Costa Sharareh Gholamin Ryan T Nitta Luiz Gustavo Dubois Marie Fève Maria Zeniou Paulo Lucas Cerqueira Coelho Elias El‐Habr Josette Cadusseau Pascale Varlet Siddhartha S Mitra Bertrand Devaux Marie‐Claude Kilhoffer Samuel H Cheshier Vivaldo Moura‐Neto Jacques Haiech Marie‐Pierre Junier Hervé Chneiweiss The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway EMBO Molecular Medicine glioma GL261 rottlerin sh PKCδ δV1.1 |
| title | The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway |
| title_full | The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway |
| title_fullStr | The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway |
| title_full_unstemmed | The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway |
| title_short | The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway |
| title_sort | anti hypertensive drug prazosin inhibits glioblastoma growth via the pkcδ dependent inhibition of the akt pathway |
| topic | glioma GL261 rottlerin sh PKCδ δV1.1 |
| url | https://doi.org/10.15252/emmm.201505421 |
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