title: 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- 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.
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine-IBPS, Paris, France Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
authors.forename: Suzana
authors.initials: S
authors.lastname: Assad Kahn
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine-IBPS, Paris, France Neurochemistry and Cell Biology Laboratory Universidade Federal da Bahia, Salvador-Bahia, Brazil.
authors.forename: Silvia Lima
authors.initials: SL
authors.lastname: Costa
authors.affiliation: Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Gholamin
authors.affiliation: Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Nitta
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine-IBPS, Paris, France Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil.
authors.forename: Luiz Gustavo
authors.initials: LG
authors.lastname: Dubois
authors.affiliation: Laboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200, Illkirch, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Fève
authors.affiliation: Laboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200, Illkirch, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Zeniou
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine-IBPS, Paris, France Neurochemistry and Cell Biology Laboratory Universidade Federal da Bahia, Salvador-Bahia, Brazil.
authors.forename: Paulo Lucas Cerqueira
authors.initials: PL
authors.lastname: Coelho
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine-IBPS, Paris, France.
authors.forename: Elias
authors.initials: E
authors.lastname: El-Habr
authors.affiliation: UMR INSERM 955-Team 10, Faculté des Sciences et Technologies UPEC, Créteil, France.
authors.forename: Josette
authors.initials: J
authors.lastname: Cadusseau
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris, France Paris Descartes University, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
authors.affiliation: Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Paris Descartes University, Paris, France Department of Neurosurgery, Sainte-Anne Hospital, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Devaux
authors.affiliation: Laboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200, Illkirch, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Kilhoffer
authors.affiliation: Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Cheshier
authors.affiliation: Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil.
authors.forename: Vivaldo
authors.initials: V
authors.lastname: Moura-Neto
authors.affiliation: Laboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200, Illkirch, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Haiech
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine-IBPS, Paris, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine-IBPS, Paris, France CNRS, UMR 8246, Neuroscience Paris Seine-IBPS, Paris, France Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine-IBPS, Paris, France herve.chneiweiss@inserm.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D058492:Drug Repositioning; D005909:Glioblastoma / Q000188:drug therapy*; D064593:Heterografts; D006801:Humans; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; C497259:Prkcd protein, mouse; D051058:Oncogene Protein v-akt; D051745:Protein Kinase C-delta; D011224:Prazosin
keywords: GL261; glioma; rottlerin; sh PKCδ; δV1.1