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Article Dans Une Revue EMBO Molecular Medicine Année : 2016

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

Résumé

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 a1-and a2B-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 PKCd-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKCd 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 hyperten-sion, inhibits glioblastoma growth through a PKCd-dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.
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hal-01297988 , version 1 (05-04-2016)

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Suzana Assad Kahn, Silvia Lima Costa, Sharareh Gholamin, Ryan T. Nitta, Gustavo Luiz Dubois, et al.. The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCd-dependent inhibition of the AKT pathway. EMBO Molecular Medicine, 2016, 8 (5), pp.511-526. ⟨10.15252/emmm.201505421⟩. ⟨hal-01297988⟩
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