| Autor: |
Assad Kahn, Suzana, Costa, Silvia Lima, Gholamin, Sharareh, Nitta, Ryan T, Dubois, Luiz Gustavo, Fève, Marie, Zeniou, Maria, Coelho, Paulo Lucas Cerqueira, El‐Habr, Elias, Cadusseau, Josette, Varlet, Pascale, Mitra, Siddhartha S, Devaux, Bertrand, Kilhoffer, Marie‐Claude, Cheshier, Samuel H, Moura‐Neto, Vivaldo, Haiech, Jacques, Junier, Marie‐Pierre, Chneiweiss, Hervé |
| Zdroj: |
EMBO Molecular Medicine; May2016, Vol. 8 Issue 5, p511-526, 16p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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