2. Academic Validation
  3. The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway

The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway

  • EMBO Mol Med. 2016 May 2;8(5):511-26. doi: 10.15252/emmm.201505421.
Suzana Assad Kahn 1,  Silvia Lima Costa 2,  Sharareh Gholamin 3,  Ryan T Nitta 3,  Luiz Gustavo Dubois 4,  Marie Fève 5,  Maria Zeniou 5,  Paulo Lucas Cerqueira Coelho 2,  Elias El-Habr 6,  Josette Cadusseau 7,  Pascale Varlet 8,  Siddhartha S Mitra 3,  Bertrand Devaux 9,  Marie-Claude Kilhoffer 5,  Samuel H Cheshier 3,  Vivaldo Moura-Neto 10,  Jacques Haiech 5,  Marie-Pierre Junier 6,  Hervé Chneiweiss 11
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 Laboratoire d'Innovation Thérapeutique, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, Université de Strasbourg/CNRS UMR7200, Illkirch, France.
  • 6 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.
  • 7 UMR INSERM 955-Team 10, Faculté des Sciences et Technologies UPEC, Créteil, France.
  • 8 Department of Neuropathology, Sainte-Anne Hospital, Paris, France Paris Descartes University, Paris, France.
  • 9 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.
  • 10 Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil.
  • 11 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.
PMID: 27138566 DOI: 10.15252/emmm.201505421
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.

Keywords

GL261; glioma; rottlerin; sh PKCδ; δV1.1.

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