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
  • 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 [email protected].
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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